The DOI matches its Crossref record; 92 of the 95 references it cites were found in a registry or an index; 43 of the 77 sources its claims cite were checked for support.
Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis
Open accessAbstract
Synaptotagmin-1 and neuronal SNARE proteins have central roles in evoked synchronous neurotransmitter release; however, it is unknown how they cooperate to trigger synaptic vesicle fusion. Here we report atomic-resolution crystal structures of Ca2+- and Mg2+-bound complexes between synaptotagmin-1 and the neuronal SNARE complex, one of which was determined with diffraction data from an X-ray free-electron laser, leading to an atomic-resolution structure with accurate rotamer assignments for many side chains. The structures reveal several interfaces, including a large, specific, Ca2+-independent and conserved interface. Tests of this interface by mutagenesis suggest that it is essential for Ca2+-triggered neurotransmitter release in mouse hippocampal neuronal synapses and for Ca2+-triggered vesicle fusion in a reconstituted system. We propose that this interface forms before Ca2+ triggering, moves en bloc as Ca2+ influx promotes the interactions between synaptotagmin-1 and the plasma membrane, and consequently remodels the membrane to promote fusion, possibly in conjunction with other interfaces.
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TL;DR
The paper reports crystal structures of Ca2+- and Mg2+-bound synaptotagmin-1–neuronal SNARE complexes, including one determined from X-ray free electron laser diffraction data, revealing a large conserved Ca2+-independent primary interface. Mutagenesis and functional assays indicate this interface is required for efficient Syt1–SNARE binding and Ca2+-triggered evoked release/fusion, supporting a model in which the C2B–SNARE unit moves en bloc upon Ca2+ influx to remodel the membrane.
Key findings
- The structures reveal three Syt1–SNARE interfaces (“primary,” “secondary,” and “tertiary”) plus a C2A–C2B interface; the primary interface is the largest, similar in both crystal forms and in Ca2+- versus Mg2+-bound structures, has relatively low B-factors, and is conserved across synaptotagmins/SNAP-25/syntaxin-1A homologs involved in fast synchronous release.
- Mutating primary-interface regions reduced Syt1 binding to syntaxin-1A/SNARE complex by ~50% for region I or region II mutants and to ~33% for the Syt1 quintuple mutant; in single-vesicle content-mixing assays, these mutants reduced vesicle association and Ca2+-triggered fusion amplitude/synchronization but did not affect spontaneous fusion, with the Syt1 quintuple reducing Ca2+-triggered synchronization to the no-Syt1 control level.
- In Syt1 cKO neurons, region I mutants retained some rescue of evoked inhibitory postsynaptic currents, whereas region II mutants were nearly non-functional; triple and quintuple mutants showed more severe phenotypes, and E295A/Y338W rescued spontaneous-release unclamping while region II mutants did not.
- XFEL data collection used 148 crystals; 113 produced 578 processable images, and the final long-unit-cell dataset used 309 images from 72 crystals. At LCLS, 61 of ~72 long-unit-cell crystals diffracted to at least 3.5 Å, versus 1 of 85 screened long-unit-cell crystals reaching 4.1 Å at APS; refined structures were at 3.50 Å (Ca2+-bound long unit cell), 3.60 Å (Ca2+-bound short unit cell), 4.10 Å (Mg2+-bound short unit cell), and 1.65 Å (Syt1 C2B quintuple mutant).
Methods
- A Syt1 C2AB–linker–SNAP-25_C chimera plus SNAP-25_N, syntaxin-1A, and synaptobrevin-2 fragments was co-expressed in E. coli, purified, and crystallized as Ca2+- and Mg2+-bound Syt1–SNARE complexes; diffraction data were collected at LCLS XFEL and APS synchrotron beamlines, and structures were determined by molecular replacement and refined with Coot/CNS/phenix.refine.
- Structure-guided mutations were validated by circular dichroism, size-exclusion chromatography, and a crystal structure of the Syt1 C2B quintuple mutant; functional tests included co-immunoprecipitation from Syt1 cKO neurons, single-vesicle content-mixing assays with full-length Syt1/SNAREs/complexin-1, and electrophysiological recordings in cultured hippocampal neurons.
- Analyses included crystallographic data/refinement statistics, interface and electrostatic-potential analysis, sequence alignments, comparison with prior smFRET histograms, quantitative immunoblotting, and counting of spontaneous versus Ca2+-triggered fusion events.
Limitations
- Stated: the XFEL diffraction data had poorer conventional merging statistics than rotation data, and it is difficult to assess their relative quality; lack of available XFEL beamtime prevented collecting a complete dataset beyond 3.5 Å. The authors also note that comparison with a prior NMR study was not possible because covalently attached lanthanide labels would likely disrupt the primary interface.
- Stated: the minimal reconstituted system lacks other factors, which may explain why the R398Q/R399Q mutant had little effect on synchronization there and why spontaneous release behavior differed between neuronal cultures and the reconstituted assay.
- Evident from the text: the crystal structures use a Syt1 C2AB fragment and truncated SNARE fragments, and the covalent linker was cleaved during crystallization; functional conclusions rely on designed mutants and may not fully capture full-length protein behavior in native membranes, although the paper argues the linker likely did not affect the final structures.
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Claims the paper makes
57 Own result · 18 Own interpretation · 17 Supported · 11 No full text of the sources · 8 Partly supported · 7 Supported so far · 6 Own method · 3 No basis given · 1 Sources not found · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In contrast, a mutant that affects the polybasic region of Syt1 (R322E, K325E) exhibited a milder phenotype as reported previously30.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Evoked release requires primary interface
What the sources say
- Partly supportedcites [30] Brewer, K. D. et al. Dynamic binding mode of a Synaptotagmin-1–SNARE complex in solution. Nature Struct. Mol. Biol. 22, 555–564 (2015) sourceExperimental — accuracy not yet measured
The Results section (‘Correlation of Syt1-SNARE complex binding with Syt1 function’; page unavailable) identifies R322E K325E as a polybasic-region double mutant and describes its impairment of neurotransmitter release as partial. It also says this mutant strongly impaired rescue of evoked release, while other double mutants had much milder effects. The source therefore supports an impairment, but not the unqualified description of this mutant’s phenotype as milder. (LLM, conf=0.82)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“All three interfaces between Syt1 and the SNARE complex fall within the range of smFRET efficiency histograms obtained previously28 (Extended Data Fig. 4).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Three distinct Syt1-SNARE interfaces
What the sources say
- Supportedcites [28] Choi, U. B. et al. Single-molecule FRET-derived model of the synaptotagmin 1-SNARE fusion complex. Nature Struct. Mol. Biol. 17, 318–324 (2010) source
The Results section, “SmFRET determines a model of the Syt1–SNARE complex,” reports previously obtained intermolecular smFRET histograms with efficiency peaks from 0.1 to 0.9. The comparison of all three interfaces with those histograms is the citing authors’ analysis, indicated by their Extended Data Fig. 4, rather than a finding attributed to this source. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Syt1 also interacts with the neuronal SNARE complex based on immunoprecipitation and pull-downs24–27, single molecule fluorescence resonance energy transfer (smFRET)28, and nuclear magnetic resonance29,30 experiments.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Introduction
What the sources say
- Not checked — no full text of the sourcecites [24] Bennett, M. K., Calakos, N. & Scheller, R. H. Syntaxin: a synaptic protein implicated in docking of synaptic vesicles at presynaptic active zones. Science 257, 255–259 (1992) source
- Not checked — no full text of the sourcecites [25] Li, C. et al. Ca2+-dependent and -independent activities of neural and non-neural synaptotagmins. Nature 375, 594–599 (1995) source
- Supportedcites [26] Pang, Z. P., Shin, O.-H., Meyer, A. C., Rosenmund, C. & Südhof, T. C. A gain-of-function mutation in synaptotagmin-1 reveals a critical role of Ca2+-dependent soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex binding in synaptic exocytosis. J. Neurosci. 26, 12556–12565 (2006) source
The Discussion reports that synaptotagmin-1 binds SNARE complexes and describes immunoprecipitation of native synaptotagmin-1 with SNARE proteins (Figures 1 and 2). This supports the interaction attributed to the source; the cited paper need not establish every technique listed alongside other citations in the sentence. (LLM, conf=0.93)
- Supportedcites [27] Rickman, C. et al. Conserved prefusion protein assembly in regulated exocytosis. Mol. Biol. Cell 17, 283–294 (2006) source
The Results section (“Complementary Binding of Two Vesicular Proteins to t-SNAREs”) reports that SYT binds the syntaxin/SNAP-25 assembly and that this interaction is not diminished when synaptobrevin joins the ternary SNARE complex. The reported binding to immobilized GST-C2AB also supports the pull-down evidence cited in the sentence. (LLM, conf=0.93)
- Supportedcites [28] Choi, U. B. et al. Single-molecule FRET-derived model of the synaptotagmin 1-SNARE fusion complex. Nature Struct. Mol. Biol. 17, 318–324 (2010) source
The Results section (“FRET efficiency distribution of SNARE-bound Syt1”) reports that Syt1 bound robustly to bilayers containing preassembled SNARE complexes. The Results section (“SmFRET determines a model of the Syt1–SNARE complex”) also describes smFRET measurements of Syt1 bound to those complexes. (LLM, conf=0.94)
- Not checked — no full text of the sourcecites [29] Dai, H., Shen, N., Araç, D. & Rizo, J. A quaternary SNARE-synaptotagmin-Ca2+-phospholipid complex in neurotransmitter release. J. Mol. Biol. 367, 848–863 (2007) source
- Supportedcites [30] Brewer, K. D. et al. Dynamic binding mode of a Synaptotagmin-1–SNARE complex in solution. Nature Struct. Mol. Biol. 22, 555–564 (2015) source
The Abstract (page not provided) describes NMR measurements of a Syt1–SNARE complex and identifies regions that mediate binding. The Results section, “The SNARE complex binds to the C2B domain polybasic region” (page not provided), reports NMR spectral shifts induced by the SNARE complex, supporting the attributed interaction. (LLM, conf=0.94)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“The effect of the Syt1 R322E, K325E mutant (Fig. 4) as well as reported observations29,30,35,44,45 suggests a functional role for the polybasic region.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Model of Syt1 mediated Ca2+ triggering
What the sources say
- Not checked — no full text of the sourcecites [29] Dai, H., Shen, N., Araç, D. & Rizo, J. A quaternary SNARE-synaptotagmin-Ca2+-phospholipid complex in neurotransmitter release. J. Mol. Biol. 367, 848–863 (2007) source
- Supportedcites [30] Brewer, K. D. et al. Dynamic binding mode of a Synaptotagmin-1–SNARE complex in solution. Nature Struct. Mol. Biol. 22, 555–564 (2015) source
The Results section (‘Correlation of Syt1-SNARE complex binding with Syt1 function’; page not provided) reports that R322E K325E strongly impaired rescue of evoked release in Syt1-knockout neurons. It links that functional effect to impaired binding involving the C2B polybasic region, supporting the claimed functional role. (LLM, conf=0.94)
- Supportedcites [35] Gaffaney, J. D., Dunning, F. M., Wang, Z., Hui, E. & Chapman, E. R. Synaptotagmin C2B domain regulates Ca2+-triggered fusion in vitro: critical residues revealed by scanning alanine mutagenesis. J. Biol. Chem. 283, 31763–31775 (2008) source
The Discussion reports that mutations including K326A, K327A, and K331A diminish Syt1’s clamping activity. It also states that previous studies demonstrated the importance of the polylysine motif for t-SNARE binding and Syt1 function in vivo. These observations support the cited point that the polybasic region has a functional role; the R322E, K325E result is the citing paper’s own Fig. 4 result. (LLM, conf=0.91)
- Supportedcites [44] Masumoto, T. et al. Ca2+-independent syntaxin binding to the C2B effector region of synaptotagmin. Mol. Cell. Neurosci. 49, 1–8 (2012) source
The Results section (“Syntaxin-binding sites on synaptotagmin”; page unavailable) reports that mutations in the C2B lysine region inhibited syntaxin binding by 80%. The Discussion (page unavailable) also links residues in that region to neurotransmitter release. These observations support a functional role for the polybasic region; the citing sentence presents the R322E/K325E result as its own finding, not as this source’s. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [45] Mackler, J. & Reist, N. Mutations in the second C2 domain of synaptotagmin disrupt synaptic transmission at Drosophila neuromuscular junctions. J. Comp. Neurol. 436, 4–16 (2001) source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Other dynamic or approximate models of the C2AB-SNARE complex were obtained by nuclear magnetic resonance (NMR)29,30, but cannot be readily compared with the previous smFRET studies28 and the results presented here because of differences in conditions, particular covalent attachment of lanthanide labels30, and lack of atomic resolution.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Introduction
What the sources say
- Not checked — no full text of the sourcecites [29] Dai, H., Shen, N., Araç, D. & Rizo, J. A quaternary SNARE-synaptotagmin-Ca2+-phospholipid complex in neurotransmitter release. J. Mol. Biol. 367, 848–863 (2007) source
- Supportedcites [30] Brewer, K. D. et al. Dynamic binding mode of a Synaptotagmin-1–SNARE complex in solution. Nature Struct. Mol. Biol. 22, 555–564 (2015) source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Supportedcites [28] Choi, U. B. et al. Single-molecule FRET-derived model of the synaptotagmin 1-SNARE fusion complex. Nature Struct. Mol. Biol. 17, 318–324 (2010) source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Every source the paper cites for this claim was checked and supports it.
In the paper
“In retrospect, the top smFRET-derived model28 and the primary interface observed in the crystal structure primarily differed in the orientation of the C2B domain.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Extended Data
What the sources say
- Supportedcites [28] Choi, U. B. et al. Single-molecule FRET-derived model of the synaptotagmin 1-SNARE fusion complex. Nature Struct. Mol. Biol. 17, 318–324 (2010) source
The citation identifies the top smFRET-derived model, rather than attributing the retrospective crystal-structure comparison to this paper. The Results section (‘SmFRET determines a model of the Syt1–SNARE complex’; page unavailable) identifies the best model and describes the position of its C2B domain. (LLM, conf=0.91)
plain- Asserted: passes — The authors put it forward as true.
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- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Moreover, subsequent work revealed major differences between using the soluble C2AB fragment and reconstituted, full-length Syt184,85.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Single vesicle-vesicle content-mixing assay
What the sources say
- Supportedcites [84] Lai, Y., Lou, X., Jho, Y., Yoon, T.-Y. & Shin, Y.-K. The synaptotagmin 1 linker may function as an electrostatic zipper that opens for docking but closes for fusion pore opening. Biochem. J. 456, 25–33 (2013) source
The Results section, “Membrane-anchored Syt1 is essential for fusion pore opening,” directly compares soluble C2AB with membrane-anchored Syt1 and finds different effects on lipid mixing without Ca2+. The Discussion reports that soluble C2AB also lacks two functions observed with reconstituted Syt1: Ca2+-independent docking and Ca2+-dependent content mixing. Page numbers were not supplied. (LLM, conf=0.94)
- Supportedcites [85] Wang, Z., Liu, H., Gu, Y. & Chapman, E. R. Reconstituted synaptotagmin I mediates vesicle docking, priming, and fusion. J. Cell Biol. 195, 1159–1170 (2011) source
The Results section ('Context-dependent mixed antagonist/agonist activity of C2AB,' Fig. 6) reports that soluble C2AB can inhibit fusion when full-length Syt1 is present but stimulates fusion in its absence. The Results ('Mutational analysis of syt during regulated fusion,' Fig. 5) also reports different effects of C2-domain mutations in C2AB assays and assays using reconstituted full-length Syt1. The supplied passages have no page numbers. (LLM, conf=0.93)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Previous reconstitutions often employed lipid mixing, rather than content mixing, between vesicles with reconstituted neuronal SNAREs21,83.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Single vesicle-vesicle content-mixing assay
What the sources say
- Not checked — no full text of the sourcecites [21] Martens, S., Kozlov, M. M. & McMahon, H. T. How synaptotagmin promotes membrane fusion. Science 316, 1205–1208 (2007) source
- Supportedcites [83] Lee, H.-K. et al. Dynamic Ca2+-dependent stimulation of vesicle fusion by membrane-anchored synaptotagmin 1. Science 328, 760–763 (2010) source
The assay description (section labeled Abstract; page unavailable) identifies reconstituted v- and t-SNARE vesicles carrying lipidic fluorescence dyes, so this paper exemplifies a reconstitution that tracks lipid mixing rather than directly measuring content mixing. The fusion-kinetics passage in the same section also acknowledges that lipid mixing can occur without proper mixing of contents. (LLM, conf=0.86)
plain- Asserted: passes — The authors put it forward as true.
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The quality indicators for the crystal structures of the Syt1-SNARE complex are well within acceptable ranges indicated by the “polygon” plot produced by phenix.refine72 and by the validation report of the deposited structures and diffraction data.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Structure determination
What the sources say
- Partly supportedcites [72] Adams, P. D. et al. PHENIX: building new software for automated crystallographic structure determination. Acta Crystallogr. D 58, 1948–1954 (2002) sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
boosted- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Recent evidence for this notion came from a reconstituted single vesicle-vesicle assay that discriminates among vesicle association, lipid mixing, and content mixing37,38,81.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Protein reconstitution for single vesicle-vesicle fusion experiments
What the sources say
- Supportedcites [37] Diao, J. et al. Synaptic proteins promote calcium-triggered fast transition from point contact to full fusion. Elife 1, e00109 (2012) source
The Materials and methods section (‘Single vesicle–vesicle content/lipid mixing system’) describes an assay using reconstituted vesicles that distinguishes docking (vesicle association) from lipid and content mixing. It also says the system differentiates docking, hemifusion, and complete fusion. (LLM, conf=0.92)
- Partly supportedcites [38] Lai, Y. et al. Complexin inhibits spontaneous release and synchronizes Ca2+-triggered synaptic vesicle fusion by distinct mechanisms. Elife 3, 1–14 (2014) sourceExperimental — accuracy not yet measured
The Materials and methods section (‘Single vesicle–vesicle content-mixing assay’) describes a reconstituted assay that distinguishes vesicle association from content-mixing fusion. It explicitly says no lipid dye was included, so this paper’s assay did not also discriminate lipid mixing. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [81] Kyoung, M. et al. In vitro system capable of differentiating fast Ca2+-triggered content mixing from lipid exchange for mechanistic studies of neurotransmitter release. Proc. Natl Acad. Sci. USA 108, E304–E313 (2011) source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Neuronal SNAREs and Syt1 represent a minimal system for Ca2+-triggered membrane fusion.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Protein reconstitution for single vesicle-vesicle fusion experiments
What the sources say
- Supportedcites [37] Diao, J. et al. Synaptic proteins promote calcium-triggered fast transition from point contact to full fusion. Elife 1, e00109 (2012) source
The Results section describes a “very minimal system consisting of only SNAREs and synaptotagmin 1” and reports that Ca2+ triggered fusion in that system. The Discussion likewise says that this combination exhibited Ca2+-triggered activity, including immediate fusion. (LLM, conf=0.94)
- Supportedcites [38] Lai, Y. et al. Complexin inhibits spontaneous release and synchronizes Ca2+-triggered synaptic vesicle fusion by distinct mechanisms. Elife 3, 1–14 (2014) source
The Abstract describes Ca2+-triggered vesicle fusion with reconstituted neuronal SNAREs and synaptotagmin-1. The Results (Figure 2 caption) report Ca2+-triggered fusion with those proteins both with and without complexin-1, supporting their description as a minimal system in this assay. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [81] Kyoung, M. et al. In vitro system capable of differentiating fast Ca2+-triggered content mixing from lipid exchange for mechanistic studies of neurotransmitter release. Proc. Natl Acad. Sci. USA 108, E304–E313 (2011) source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“the top smFRET derived model predicted the approximate location primary interface on the neuronal SNARE (see Fig. 4c in ref. 28).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Extended Data
What the sources say
- Supportedcites [28] Choi, U. B. et al. Single-molecule FRET-derived model of the synaptotagmin 1-SNARE fusion complex. Nature Struct. Mol. Biol. 17, 318–324 (2010) source
The Results section identifies Fig. 4c as the best smFRET-derived model and places the Syt1–SNARE interaction at the middle of the SNARE complex on its SNAP-25 side. The Discussion likewise describes the central SNARE region as mediating Syt1 binding, supporting the claimed approximate interface location. (LLM, conf=0.92)
plain- Asserted: passes — The authors put it forward as true.
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- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“The R values of the refined structures (Extended Data Table 1) are well within the range that is typical at the corresponding resolutions74.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Structure determination
What the sources say
- Supportedcites [74] Urzhumtseva, L., Afonine, P. V., Adams, P. D. & Urzhumtsev, A. Crystallographic model quality at a glance. Acta Crystallogr. D 65, 297–300 (2009) source
The Introduction explains that R factors can be judged against the distribution of values for structures refined at the same resolution. The Models for comparison section says models are compared by default with structures at the same resolution. The cited paper supports the resolution-matched benchmark; the citing document’s Extended Data Table 1 supplies the R values being assessed. (LLM, conf=0.88)
boosted- Asserted: passes — The authors put it forward as true.
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- Supported
In the paper
“The interacting residues of the primary interface are conserved across different species for synaptotagmins (Syt1, Syt2, Syt9, ref. 8), SNAP-25, and syntaxin-1A homologs involved in fast synchronous release (Extended Data Fig. 6).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Three distinct Syt1-SNARE interfaces
What the sources say
- Not checked — no full text of the sourcecites [8] Xu, J., Mashimo, T. & Südhof, T. C. Synaptotagmin-1, -2, and -9: Ca2+ sensors for fast release that specify distinct presynaptic properties in subsets of neurons. Neuron 54, 567–581 (2007) source
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The triple mutant (R281A, R398A, R399A), and the quintuple mutant that combines mutations in both regions showed even more severe phenotypes.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Evoked release requires primary interface
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The interactions that form the tertiary interface are primarily ionic, involving residues Syt1 R199 and R233, syntaxin-1A D218, and synaptobrevin-2 D57 (Fig. 1b) with well resolved electron density.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Three distinct Syt1-SNARE interfaces
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here we report atomic-resolution crystal structures of Ca2+- and Mg2+-bound complexes between synaptotagmin-1 and the neuronal SNARE complex, one of which was determined with diffraction data from an X-ray free electron laser, leading to an atomic-resolution structure with accurate rotamer assignments for many sidechains.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Abstract
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“In particular, the “Syt1 quintuple” mutant significantly reduced Ca2+-triggered synchronization to the control level without Syt1.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > The primary interface is critical
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“The Syt1 mutants disrupting the interface between the SNARE complex and Syt1 as seen by co-immunoprecipitation (Figs. 3b, c) also reduced vesicle association to similar degrees for the four different mutants (left group of mutants in Fig. 3d).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > The primary interface is critical
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“The X-ray free electron laser (XFEL) of the Linac Coherent Light Source (LCLS) at SLAC National Accelerator Laboratory yielded substantially higher-quality diffraction data than the Advanced Photon Source (APS) NE-CAT microfocus synchrotron beamline at Argonne National Laboratory from similar crystals of the long unit cell crystal form (Extended Data Figs. 2a, b).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Structure of the Syt1-SNARE complex
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In the paper
“The structures revealed several interfaces, including a large, specific, Ca2+-independent, and conserved interface.”
- Also stated in: § Three distinct Syt1-SNARE interfaces · plain
“The crystal structures of the Syt1-SNARE complex reveal three interfaces between the SNARE complex and the Syt1 C2A and C2B domains (referred to as “primary”, “secondary”, and “tertiary”), as well as an interface between Syt1 C2 domains (referred to as “C2A-C2B interface”, Figs. 1a, b, Supplementary Videos 1 and 2).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Abstract
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- Also stated in: § Three distinct Syt1-SNARE interfaces · plain
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In the paper
“There were no differences in spontaneous miniature IPSC amplitudes between WT and mutant rescues (Fig. 4g).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Evoked release requires primary interface
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“The combined surface of the Syt1 C2B-SNARE unit forms a flat face with an extensive pattern of positive charges (Fig. 5b) that includes the polybasic region of Syt1 as well as basic residues at the membrane-proximal side of the neuronal SNARE complex.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Model of Syt1 mediated Ca2+ triggering
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In the paper
“Our reconstituted assay also allowed testing of the interacting SNAP-25 residues (middle group of mutants in Fig. 3d), showing significant reduction of vesicle association as well.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > The primary interface is critical
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“The C2B domain forming the secondary interface is slightly rotated with respect to the SNARE complex between the two crystal forms and between the Ca2+- and Mg2+-bound crystal structures (Extended Data Figs. 5b, d), although the interactions at the secondary interface itself are similar.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Three distinct Syt1-SNARE interfaces
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“There are two essentially identical instances of the primary interface formed between Syt1 C2B domains and the SNARE complex in the long unit cell crystal form (Figs. 1c, d).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Three distinct Syt1-SNARE interfaces
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“In contrast, the interacting residues show variation among other synaptotagmin, SNAP-25, and syntaxin homologs that are not known to be involved in fast synchronous release.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Three distinct Syt1-SNARE interfaces
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“Syt1 and SNAP-25 mutants are well folded”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Extended Data
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“XFEL diffraction tests of hydrated crystals at room temperature did not show any marked improvement in comparison to cryo-preserved crystals, at least in terms of visible limiting resolution of the observed diffraction pattern.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > XFEL data collection and processing
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“The Syt1 C2B (I′) domain is rotated by 16 degrees between the two crystal forms”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Extended Data
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In the paper
“The crystal structure of the quintuple mutant is very similar to that of WT C2B (PDB code 2YOA) (main chain RMSD 0.43 Å, Extended Data Fig. 7b).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Design of mutations to disrupt the primary interface
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In the paper
“Moreover, in the LCLS XFEL crystal structure there is clear electron density for 19 Ca2+ bound to the Ca2+ binding sites of the Syt1 C2 domains and to a few additional sites on the surfaces of Syt1 and SNARE molecules (Extended Data Table 1).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > The LCLS XFEL produced superior electron density maps
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In the paper
“Even with B-factor sharpening, the electron density map of the long unit cell crystal form collected at the LCLS XFEL is superior to that of the short unit cell crystal form collected at the APS NE-CAT microfocus synchrotron beamline.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Extended Data
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In the paper
“The diffraction data obtained at the LCLS XFEL extended to substantially higher resolution than data collected at the APS NE-CAT microfocus synchrotron beamline from similar crystals of the long cell form (Extended Data Figs. 2a, b).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > The LCLS XFEL produced superior electron density maps
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In the paper
“Crystallization trials performed by mixing the neuronal SNARE complex and Syt1 C2AB fragments were unsuccessful, probably due to the weak affinity between the two components and the aggregation propensity at higher concentrations, especially in the presence of Ca2+.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Crystallization of the Ca2+-bound Syt1-SNARE complex
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In the paper
“The iterative scaling and post-refinement approach utilized by PRIME allowed the construction of a complete diffraction dataset from the relatively small number of diffraction images.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > XFEL data collection and processing
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In the paper
“61 out of ~72 crystals in the long unit cell crystal form diffracted to at least 3.5 Å resolution at the LCLS XFEL”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Extended Data
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“The complex with a longer 37 amino acid linker (Syt1-SNARE37aa-linker) was more soluble in SEC buffer compared to the one with the shorter 23 amino acid linker.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Crystallization of the Ca2+-bound Syt1-SNARE complex
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In the paper
“In contrast, electron density could be identified for only 7 Ca2+ in the short unit cell crystal form collected at the APS synchrotron.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > The LCLS XFEL produced superior electron density maps
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In the paper
“Interestingly, residues Syt1 R281, K288 and R398 are involved in both the primary (Fig. 2) and secondary interfaces.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Extended Data
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In the paper
“The lower left sub-panel shows a close-up view of the primary interface, indicating that it is very similar in both the Ca2+- and Mg2+-bound crystal structures.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Extended Data
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In the paper
“Two Syt1 C2AB fragments (distinguished by the designators I and I′) bind to the same SNARE complex in the asymmetric unit”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Extended Data
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In the paper
“The Syt1 C2B domain that forms the secondary interface (light blue shaded disk) is rotated by 19 degrees between the Ca2+- and Mg2+-bound complexes.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Extended Data
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In the paper
“The red dashed oval indicates the “missing” Syt1 C2AB fragment compared to the short unit cell crystal form”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Extended Data
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In the paper
“Asymmetric unit of the Ca2+-bound Syt1-SNARE complex in the short unit cell crystal form at 3.6 Å resolution using diffraction data collected at the APS NE-CAT microfocus synchrotron beamline”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Extended Data
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In the paper
“In addition to its role in evoked synchronous release, Syt1 also clamps the frequency of miniature spontaneous events11–13.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Introduction
What the sources say
- Not checked — no full text of the sourcecites [11] Yoshihara, M. & Littleton, J. T. Synaptotagmin I functions as a calcium sensor to synchronize neurotransmitter release. Neuron 36, 897–908 (2002) source
- Not checked — no full text of the sourcecites [12] Maximov, A. & Südhof, T. C. Autonomous function of synaptotagmin 1 in triggering synchronous release independent of asynchronous release. Neuron 48, 547–554 (2005) source
- Not checked — no full text of the sourcecites [13] Kochubey, O. & Schneggenburger, R. Synaptotagmin increases the dynamic range of synapses by driving Ca2+-evoked release and by clamping a near-linear remaining Ca2+ sensor. Neuron 69, 736–748 (2011) source
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In the paper
“Among these isoforms, synaptotagmin-1 (Syt1) is a Ca2+ sensor for evoked synchronous neurotransmitter release7.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Introduction
What the sources say
- Not checked — no full text of the sourcecites [7] Geppert, M. et al. Synaptotagmin I: a major Ca2+ sensor for transmitter release at a central synapse. Cell 79, 717–727 (1994) source
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In the paper
“Thus, as expected, mutations on both the Syt1 and SNARE sides of the primary interface reduce the interaction between them.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > The primary interface is critical
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In the paper
“Our crystal structures of the Syt1-SNARE complex now suggest a parsimonious mechanism that involves a concerted action of the unit consisting of the Syt1 C2B domain and the SNARE complex (Fig. 5a).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Model of Syt1 mediated Ca2+ triggering
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- The authors state this as an assumption: Prior to Ca2+ influx, there is a membrane juxtaposed, hemifusion-free state, the likely starting state for fast Ca2+ triggered fusion, and a partially folded trans-SNARE complex.
- The authors state this as an assumption: The Syt1 C2B-SNARE unit can assemble in the pre-Ca2+ state.
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In the paper
“It is likely that Syt1 engages in multiple functionally relevant interactions with neuronal SNARE complexes, including the other interfaces found in our crystal structures.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Model of Syt1 mediated Ca2+ triggering
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In the paper
“These results suggest that both regions are required for efficient Syt1-SNARE binding.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > The primary interface is critical
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In the paper
“The simultaneous membrane interactions of the Ca2+ binding loops, of the polybasic region, and of membrane-proximal region of the SNARE complex would therefore require a deformation of the plasma membrane.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Model of Syt1 mediated Ca2+ triggering
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- The authors state this as an assumption: Prior to Ca2+ influx, there is a membrane juxtaposed, hemifusion-free state, the likely starting state for fast Ca2+ triggered fusion, and a partially folded trans-SNARE complex.
- The authors state this as an assumption: The Syt1 C2B-SNARE unit can assemble in the pre-Ca2+ state.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We designed mutations of the critical interacting residues of the primary interface based on the crystal structure and verified that all mutants result in properly folded Syt1 and SNARE complex (Methods and Extended Data Fig. 7).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > The primary interface is critical
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In the paper
“The membrane-synaptotagmin interaction has functional significance since the Ca2+ affinity of Syt1 for binding to anionic membranes and the Ca2+ sensitivity of neurotransmitter release are tightly correlated16,18.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Introduction
What the sources say
- Not checked — no full text of the sourcecites [16] Fernández-Chacón, R. et al. Synaptotagmin I functions as a calcium regulator of release probability. Nature 410, 41–49 (2001) source
- Not checked — no full text of the sourcecites [18] Rhee, J.-S. et al. Augmenting neurotransmitter release by enhancing the apparent Ca2+ affinity of synaptotagmin 1. Proc. Natl Acad. Sci. USA 102, 18664–18669 (2005) source
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In the paper
“We propose that the Syt1 C2B-SNARE unit moves en bloc as an entity upon Ca2+-triggering.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Model of Syt1 mediated Ca2+ triggering
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- The authors state this as an assumption: Prior to Ca2+ influx, there is a membrane juxtaposed, hemifusion-free state, the likely starting state for fast Ca2+ triggered fusion, and a partially folded trans-SNARE complex.
- The authors state this as an assumption: The Syt1 C2B-SNARE unit can assemble in the pre-Ca2+ state.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We verified that the Syt1 mutants are properly folded by measuring circular dichroism (CD) spectra and thermal denaturation curves (Extended Data Fig. 7a), crystal structure determination of the Syt1 C2B quintuple mutant (R281A, E295A, Y338W, R398A, R399A) (Extended Data Figs. 7b–d, Extended Data Table 1), and size exclusion chromatography of Syt1 (Extended Data Fig. 7e).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Design of mutations to disrupt the primary interface
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In the paper
“We also established that the mutated SNARE complexes form properly (Extended Data Fig. 7f).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Design of mutations to disrupt the primary interface
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In the paper
“Thus, our improved single vesicle-vesicle assay enables one to monitor the association of SV vesicles, spontaneous, and Ca2+ triggered fusion events during the same data acquisition.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Single vesicle-vesicle content-mixing assay
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, the crystal structures are likely not affected by the initial presence of the linker.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Crystallization of the Ca2+-bound Syt1-SNARE complex
hedged- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Nonetheless, the 40 fs laser pulse enables the so-called “diffraction before destruction” data collection58,59, whereby the diffraction pattern is recorded before the sample is destroyed.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > XFEL data collection and processing
What the sources say
- Not checked — no full text of the sourcecites [58] Neutze, R., Wouts, R., van der Spoel, D., Weckert, E. & Hajdu, J. Potential for biomolecular imaging with femtosecond X-ray pulses. Nature 406, 752–757 (2000) source
- Not checked — no full text of the sourcecites [59] Solem, J. C. Imaging biological specimens with high-intensity soft x rays. J. Opt. Soc. Am. B 3, 1551 (1986) source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The label at position A61 would have disrupted the tertiary interfaces between the C2A domain and the SNARE complex, explaining the discrepancy for these labels (indicated by open triangles).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Extended Data
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Note that due to the presence of transitions between different states the histogram reflect a combined effect of interaction interfaces.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Extended Data
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 49
- Probably not a substantial claim. 20
- The quote only partly states this claim. 1
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Syt1 binds in a Ca2+-dependent manner to anionic membranes; during binding, anionic phospholipids and synaptotagmin C2 domains together coordinate calcium14–17.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Introduction
What the sources say
- Not checked — no full text of the sourcecites [14] Davletov, B. A. & Südhof, T. C. A single C2 domain from synaptotagmin I is sufficient for high affinity Ca2+/phospholipid binding. J. Biol. Chem. 268, 26386–26390 (1993) source
- Not checked — no full text of the sourcecites [15] Brose, N., Petrenko, A. G., Südhof, T. C. & Jahn, R. Synaptotagmin: a calcium sensor on the synaptic vesicle surface. Science 256, 1021–1025 (1992) source
- Not checked — no full text of the sourcecites [16] Fernández-Chacón, R. et al. Synaptotagmin I functions as a calcium regulator of release probability. Nature 410, 41–49 (2001) source
- Supportedcites [17] Vrljic, M. et al. Post-translational modifications and lipid binding profile of insect cell-expressed full-length mammalian synaptotagmin 1. Biochemistry 50, 9998–10012 (2011) source
The Discussion states that Syt1 binds anionic phospholipids in a Ca2+-dependent manner, with calcium coordinated between its Ca2+-binding loops and anionic phospholipid headgroups. The Results section (“Full-Length Syt1 Is Folded”) likewise describes calcium coordination involving the C2A and C2B domains and anionic lipids. Page numbers were not supplied. (LLM, conf=0.95)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“We note that spontaneous release observed in our reconstituted system38 reflects the fusion probability at exactly zero Ca2+ concentration (that is, in absence of a Ca2+-sensor for mini-release) whereas spontaneous release in neurons is driven by resting Ca2+-concentrations and is largely blocked by removing all calcium41.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Evoked release requires primary interface
What the sources say
- Supportedcites [38] Lai, Y. et al. Complexin inhibits spontaneous release and synchronizes Ca2+-triggered synaptic vesicle fusion by distinct mechanisms. Elife 3, 1–14 (2014) source
The citation to this paper is attached to the reconstituted-system claim, not the subsequent claim about neurons. The Results and Materials and methods describe spontaneous fusion before Ca2+ injection, with Ca2+ removed from the preparation and sample chamber. This supports fusion under nominally calcium-free conditions, though the paper does not establish a mathematically exact zero concentration. (LLM, conf=0.87)
- Partly supportedcites [41] Xu, J., Pang, Z. P., Shin, O.-H. & Südhof, T. C. Synaptotagmin-1 functions as a Ca2+ sensor for spontaneous release. Nature Neurosci. 12, 759–766 (2009) sourceExperimental — accuracy not yet measured
The Results section (“Spontaneous release is Ca2+-dependent”) reports that intracellular Ca2+ chelation blocked more than 95% of spontaneous mIPSCs, supporting the claim about removing calcium. But the Discussion says release is likely triggered by Ca2+ sparks rather than resting presynaptic Ca2+ concentrations. The citation is attached to the neuronal-release claim, not the description of the reconstituted system. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Moreover, in contrast to the tens of thousands to millions of crystals typically used in XFEL-based crystallography experiments34, we obtained a reasonably complete data set from a few hundred images using 148 crystals (Methods).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Structure of the Syt1-SNARE complex
What the sources say
- Supportedcites [34] Redecke, L. et al. Natively inhibited Trypanosoma brucei cathepsin B structure determined by using an X-ray laser. Science 339, 227–230 (2013) source
Citation 34 supports the comparison with large XFEL crystallography experiments, not the citing authors’ own result using 148 crystals. The source reports 178,875 indexed diffraction patterns from individual microcrystals, consistent with the cited scale of crystal use. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Interestingly, the region I mutants retained some rescue ability, in contrast to region II mutants that were nearly non-functional (Figs. 4a, b), including the R398Q, R399Q mutant as previously reported36.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Evoked release requires primary interface
What the sources say
- Supportedcites [36] Xue, M., Ma, C., Craig, T. K., Rosenmund, C. & Rizo, J. The Janus-faced nature of the C2B domain is fundamental for synaptotagmin-1 function. Nature Struct. Mol. Biol. 15, 1160–1168 (2008) source
The citation is attached specifically to the previously reported R398Q,R399Q result, not to the citing authors’ region I versus region II comparison. In Results, “The two C2B domain bottom arginines are crucial for release” (Fig. 2), the source reports that the double mutation practically abolished rescue activity. The Discussion notes weak residual activity under high-frequency stimulation, consistent with “nearly non-functional.” (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Upon Ca2+ binding to the Syt1 C2B domain, the Ca2+ binding loops partially insert into the membrane23 with a preference for membrane curvature20,21, possibly supported by ionic interactions via the polybasic region and with continuing maintenance of the Syt1-SNARE interface.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Model of Syt1 mediated Ca2+ triggering
What the sources say
- Not checked — no full text of the sourcecites [23] Rufener, E., Frazier, A. A., Wieser, C. M., Hinderliter, A. & Cafiso, D. S. Membrane-bound orientation and position of the synaptotagmin C2B domain determined by site-directed spin labeling. Biochemistry 44, 18–28 (2005) source
- Partly supportedcites [20] Hui, E., Johnson, C. P., Yao, J., Dunning, F. M. & Chapman, E. R. Synaptotagmin-mediated bending of the target membrane is a critical step in Ca2+-regulated fusion. Cell 138, 709–721 (2009) sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites [21] Martens, S., Kozlov, M. M. & McMahon, H. T. How synaptotagmin promotes membrane fusion. Science 316, 1205–1208 (2007) source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
Every source the paper cites for this claim was checked and supports it.
In the paper
“In a recent study, lanthanide labels were covalently attached to SNAP-25 residues 41 and 166 for pseudocontact chemical shift NMR measurements in the presence of 125 thiocyanate30; these covalent labels would likely disrupt the primary interface (Fig. 2c), so it is not possible to compare our crystal structures with this NMR study.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Three distinct Syt1-SNARE interfaces
What the sources say
- Supportedcites [30] Brewer, K. D. et al. Dynamic binding mode of a Synaptotagmin-1–SNARE complex in solution. Nature Struct. Mol. Biol. 22, 555–564 (2015) source
The citation is attached to the description of the NMR study, not to the citing authors’ subsequent inference about interface disruption and crystal-structure comparison. The Results section reports lanthanide-tagged SNAP-25 at residues 41 and 166 for pseudocontact-shift measurements; Online Methods specifies 125 mM KSCN and describes labeling the protein before SNARE-complex assembly. (LLM, conf=0.92)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The observed smFRET histograms28 suggested several possible interfaces between Syt1 and the SNARE complex.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Introduction
What the sources say
- Partly supportedcites [28] Choi, U. B. et al. Single-molecule FRET-derived model of the synaptotagmin 1-SNARE fusion complex. Nature Struct. Mol. Biol. 17, 318–324 (2010) sourceExperimental — accuracy not yet measured
The Discussion (page not provided) says that broad, multi-peaked intermolecular smFRET distributions suggest multiple conformations of the Syt1–SNARE complex. It does not say that the histograms suggest several distinct binding interfaces; the Results instead describe a dominant modeled interface. (LLM, conf=0.82)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“A gain-of-function mutation in the Ca2+-binding region of the C2A domain suggested that the Syt1-SNARE interaction may be functionally important26, but the molecular basis and the significance of the interaction between Syt1 and the SNARE complex remain unknown.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Introduction
What the sources say
- Supportedcites [26] Pang, Z. P., Shin, O.-H., Meyer, A. C., Rosenmund, C. & Südhof, T. C. A gain-of-function mutation in synaptotagmin-1 reveals a critical role of Ca2+-dependent soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex binding in synaptic exocytosis. J. Neurosci. 26, 12556–12565 (2006) source
The Introduction identifies D232N as a mutation in the Ca2+-binding site of the C2A domain. The Results report that it selectively enhances Ca2+-dependent Syt1–SNARE binding, and the Discussion links that change to increased neurotransmitter release, supporting the claim of functional importance. Page numbers are not available in our copy. (LLM, conf=0.94)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Interestingly, the gain-of-function mutation D232N in the Ca2+-binding region of the C2A domain26 is close to the tertiary interface and it is also part of the C2A-C2B interface (Fig. 1b).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Model of Syt1 mediated Ca2+ triggering
What the sources say
- Supportedcites [26] Pang, Z. P., Shin, O.-H., Meyer, A. C., Rosenmund, C. & Südhof, T. C. A gain-of-function mutation in synaptotagmin-1 reveals a critical role of Ca2+-dependent soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex binding in synaptic exocytosis. J. Neurosci. 26, 12556–12565 (2006) source
The Introduction identifies D232N as a mutation in the Ca²⁺-binding site of the C2A domain, and the results report that it enhances Ca²⁺-dependent SNARE binding. In the citing sentence, citation 26 follows that identification; the statements about the tertiary and C2A–C2B interfaces follow the citation and refer to the citing paper’s Fig. 1b, so they are not attributed to this source. (LLM, conf=0.90)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The palmitoylated cysteine residues of SNAP-25 would be able to interact with the plasma membrane, and the membrane-proximal side of syntaxin is closely juxtaposed with the membrane, as inferred by the requirement of tight membrane-coupling of syntaxin for evoked release47.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Model of Syt1 mediated Ca2+ triggering
What the sources say
- Partly supportedcites [47] Zhou, P., Bacaj, T., Yang, X., Pang, Z. P. & Südhof, T. C. Lipid-anchored SNAREs lacking transmembrane regions fully support membrane fusion during neurotransmitter release. Neuron 80, 470–483 (2013) sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“More importantly, assays based on lipid mixing alone can produce misleading results since lipid mixing can occur without content mixing86.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Single vesicle-vesicle content-mixing assay
What the sources say
- Supportedcites [86] Zick, M. & Wickner, W. T. A distinct tethering step is vital for vacuole membrane fusion. Elife 3, e03251 (2014) source
The Results explain that hemifusion or lysis followed by membrane re-annealing can produce lipid mixing detected by lipid-based assays, making a protected lumenal-content assay important. The Discussion also reports lipid mixing with substantially less content mixing under the same reaction condition. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Ramachandran analysis with MolProbity75 indicated that 98% of the residues are in the favored regions and none are in disallowed regions.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Structure determination
What the sources say
- Supportedcites [75] Chen, V. B. et al. MolProbity: All-atom structure validation for macromolecular crystallography. Acta Crystallogr. D 66, 12–21 (2010) source
The citation identifies MolProbity as the tool used for Ramachandran analysis, not as the source of the quintuple mutant’s results. The Validation analyses section describes MolProbity’s Ramachandran evaluation and says its summary reports the percentage of residues in favored conformations and the percentage of outliers. (LLM, conf=0.92)
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Moreover, addition of complexin-1 greatly enhanced Ca2+-triggered amplitude and synchronization, and suppressed spontaneous release in this system38.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Protein reconstitution for single vesicle-vesicle fusion experiments
What the sources say
- Supportedcites [38] Lai, Y. et al. Complexin inhibits spontaneous release and synchronizes Ca2+-triggered synaptic vesicle fusion by distinct mechanisms. Elife 3, 1–14 (2014) source
The Results passage reports that adding complexin-1 increased the amplitude and decay rate of Ca2+-triggered fusion, indicating greater synchronization. It also reports a lower probability of spontaneous fusion with complexin-1 than without it in the paper’s vesicle-fusion assay. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“The size distributions of the SV and PM vesicles were analyzed by cryo-EM, as described previously37.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Protein reconstitution for single vesicle-vesicle fusion experiments
What the sources say
- Supportedcites [37] Diao, J. et al. Synaptic proteins promote calcium-triggered fast transition from point contact to full fusion. Elife 1, e00109 (2012) source
The Results section identifies the donor and acceptor vesicles as liposomes designed to mimic synaptic vesicles and the plasma membrane. The Materials and methods section (‘Measurement of vesicle diameters’; page not available) describes calculating vesicle-size distribution histograms from cryo-EM images. The histograms pool vesicles rather than reporting separate distributions for the two types. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Our single vesicle-vesicle assay thus uses full-length Syt1 and it monitors content mixing, a correlate for neurotransmitter release37,38,81.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Single vesicle-vesicle content-mixing assay
What the sources say
- Supportedcites [37] Diao, J. et al. Synaptic proteins promote calcium-triggered fast transition from point contact to full fusion. Elife 1, e00109 (2012) source
The Results section, under “Ca2+-triggered fusion with SNAREs and synaptotagmin 1,” states that the single vesicle–vesicle assay reconstituted full-length synaptotagmin 1 and monitored content mixing. The Materials and methods section, under “Single vesicle–vesicle content/lipid mixing system,” explains that its content dye is only slightly larger than neurotransmitters such as glutamate or serotonin, supporting content mixing as a correlate of neurotransmitter release. (LLM, conf=0.92)
- Supportedcites [38] Lai, Y. et al. Complexin inhibits spontaneous release and synchronizes Ca2+-triggered synaptic vesicle fusion by distinct mechanisms. Elife 3, 1–14 (2014) source
The Results (Figure 2 caption; page not provided) explicitly describe the assay as using full-length synaptotagmin-1. Materials and methods (“Single vesicle–vesicle content-mixing assay”; page not provided) says it measures exchange of vesicle contents as a correlate of neurotransmitter release. (LLM, conf=0.94)
- Not checked — no full text of the sourcecites [81] Kyoung, M. et al. In vitro system capable of differentiating fast Ca2+-triggered content mixing from lipid exchange for mechanistic studies of neurotransmitter release. Proc. Natl Acad. Sci. USA 108, E304–E313 (2011) source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“A variety of complexin-1 truncations and mutations qualitatively reproduced effects observed in neuronal cultures for both spontaneous and Ca2+-triggered release38, lending credence to this reconstituted system to investigate mechanistic questions.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Protein reconstitution for single vesicle-vesicle fusion experiments
What the sources say
- Supportedcites [38] Lai, Y. et al. Complexin inhibits spontaneous release and synchronizes Ca2+-triggered synaptic vesicle fusion by distinct mechanisms. Elife 3, 1–14 (2014) source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Ramachandran analysis with MolProbity75 indicated that 98% of the residues are in the favored regions and none are in disallowed regions for both the Ca2+- and Mg2+-bound Syt1-SNARE complexes in the short unit cell crystal form”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Structure determination
What the sources say
- Supportedcites [75] Chen, V. B. et al. MolProbity: All-atom structure validation for macromolecular crystallography. Acta Crystallogr. D 66, 12–21 (2010) source
The citation identifies MolProbity as the tool used for Ramachandran analysis. The paper’s “Torsion-angle combinations” section says MolProbity evaluates Ramachandran angles and reports percentages of favored conformations and outliers. The 98% result for the Syt1-SNARE complexes is presented as the citing authors’ analysis, not as a finding attributed to this source. (LLM, conf=0.93)
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“We note that similar improvements in limiting resolution of XFEL versus synchrotron diffraction images have been observed for GPCRs60.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > The LCLS XFEL produced superior electron density maps
What the sources say
- Supportedcites [60] Cohen, A. E. et al. Goniometer-based femtosecond crystallography with X-ray free electron lasers. Proc. Natl Acad. Sci. USA 111, 17122–17127 (2014) source
The Raster Data Collection section reports improved diffraction resolution for β2-adrenoreceptor, a GPCR, at the XFEL: the best image reached 2.3 Å, versus 2.9 Å for crystals from the same batch at a synchrotron. This supports the cited comparison, although the Discussion notes that improvements were not observed for every crystal tested. (LLM, conf=0.94)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“and that 97% of the residues are in the favored regions and none are in disallowed regions for the Ca2+-bound Syt1-SNARE complex in the long unit cell crystal form.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Structure determination
What the sources say
- Partly supportedcites [75] Chen, V. B. et al. MolProbity: All-atom structure validation for macromolecular crystallography. Acta Crystallogr. D 66, 12–21 (2010) sourceExperimental — accuracy not yet measured
The 'Torsion-angle combinations: updated Ramachandran and rotamer analyses' section (page not specified) confirms that MolProbity evaluates Ramachandran conformations and reports percentages of favored residues and outliers. It does not report an analysis of the Ca2+-bound Syt1-SNARE complex or substantiate the claimed 97% favored and zero disallowed residues. (LLM, conf=0.87)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The C2A domain that forms the tertiary interface is in the same orientation in both crystal forms and in the Ca2+- and Mg2+-bound crystal structures (Extended Data Figs. 5c, d) and the interacting side chains are in similar positions.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Three distinct Syt1-SNARE interfaces
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In the paper
“The residues involved in the primary interface have relatively low temperature factors, among the lowest in these structures (Extended Data Fig. 5e), and the electron densities of the sidechains that form this interface are well-defined (Figs. 2c, d), suggesting a specific interaction.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Three distinct Syt1-SNARE interfaces
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In the paper
“The secondary interface involves another Syt1 C2B domain and the SNARE complex, while the tertiary interface involves a Syt1 C2A domain and the SNARE complex (Fig. 1b).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Three distinct Syt1-SNARE interfaces
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In the paper
“The structures revealed several interfaces, including a large, specific, Ca2+-independent, and conserved interface.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Abstract
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In the paper
“The largest, primary interface between the Syt1 C2B domain and the SNARE complex is very similar in both complexes (Fig. 1b) and in both crystal forms (Extended Data Fig. 5a), suggesting that it is not affected by crystal packing.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Three distinct Syt1-SNARE interfaces
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In the paper
“As expected7, removal of Syt1 abolished synchronous release monitored by recording evoked inhibitory postsynaptic currents (eIPSCs), a phenotype that can be rescued by re-introduction of WT but not mutant Syt1 cDNA (Figs. 4a, b).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Evoked release requires primary interface
What the sources say
- Not checked — no full text of the sourcecites [7] Geppert, M. et al. Synaptotagmin I: a major Ca2+ sensor for transmitter release at a central synapse. Cell 79, 717–727 (1994) source
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In the paper
“The electron density maps obtained from the XFEL diffraction data were notably superior to those of the synchrotron datasets (Methods). In particular, the electron density maps calculated from the XFEL data set were of sufficient quality to obtain accurate rotamers for most sidechains, including those at the interfaces between molecules (Extended Data Figs. 2d–f).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Structure of the Syt1-SNARE complex
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In the paper
“We divide the primary interface into two regions (Fig. 2) dominated by polar interactions: region I comprises SNAP-25 E37, K40, N159, M163, D166 and Syt1 E295, K297, N336 and Y338; region II comprises SNAP-25 D51, E52, E55, syntaxin-1A D231, E234, E238, and Syt1 R281, K288, R398, and R399.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > The conserved primary interface
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In the paper
“Interestingly, the E295A, Y338W mutant could rescue this phenotype while the region II mutants (or combinations thereof) could not (Figs. 4f, g).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Evoked release requires primary interface
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In the paper
“Here we report atomic-resolution crystal structures of Ca2+- and Mg2+-bound complexes between synaptotagmin-1 and the neuronal SNARE complex, one of which was determined with diffraction data from an X-ray free electron laser, leading to an atomic-resolution structure with accurate rotamer assignments for many sidechains.”
- Also stated in: § Introduction · plain
“Here we report atomic-resolution crystal structures of a Syt1-SNARE complex in two different crystal forms and in the presence of either Ca2+ or Mg2+.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Abstract
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- Also stated in: § Introduction · plain
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In the paper
“The primary interface is also very similar in the Ca2+-bound as well as in the Mg2+-bound crystal structures (Extended Data Fig. 5d), implying a Ca2+-independent interface.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Three distinct Syt1-SNARE interfaces
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In the paper
“Mutation of either regions I and II of the primary interface reduced Syt1 binding to syntaxin-1A/SNARE complex by ~50%, and simultaneous mutation of both regions (“Syt1 quintuple”) reduced binding to ~33% as compared to a Syt1 WT construct introduced in the same manner (Figs. 3b, c).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > The primary interface is critical
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In the paper
“The SNARE complex is positively charged and Syt1 is negatively charged in region I, whereas the opposite is observed for region II.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > The conserved primary interface
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In the paper
“All Syt1 mutants underwent facilitation and the severity of the phenotype for each mutant correlated well with the results for single evoked release.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Evoked release requires primary interface
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In the paper
“We observed no effect on both spontaneous and Ca2+-triggered fusion, and only a mild effect on vesicle association (Figs. 3d–g, right group of mutants), suggesting that the functionally important interactions between Syt1 and the SNARE complex are not affected by ionic shielding.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > The primary interface is critical
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In the paper
“During high frequency stimulation, WT cultured hippocampal neurons displayed depression while Syt1 cKO neurons showed asynchronous release with robust facilitation (Figs. 4c–e).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Evoked release requires primary interface
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In the paper
“Likewise, both groups of mutants reduce the amplitude and decrease the synchronization of Ca2+-triggered fusion, but they do not affect spontaneous fusion (Figs. 3e–g).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > The primary interface is critical
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In the paper
“There were consistently two crystal forms in the same drop with identical morphology, referred to as “short unit cell” crystal form and “long unit cell” crystal form, respectively.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Crystallization of the Ca2+-bound Syt1-SNARE complex
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In the paper
“During data collection we observed that improved diffraction quality could be achieved by placing consecutive shots far apart (i.e., across the length of the crystal from one another), then later “filling” between the first and second shots in the same “shuttling” manner.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > XFEL data collection and processing
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In the paper
“Only one out of 85 screened crystals in the long unit cell crystal form diffracted to 4.1 Å resolution at the APS NE-CAT microfocus synchrotron beamline”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Extended Data
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In the paper
“Exposure to Cre-recombinase results in the total absence of synchronous release which is typical for Syt1 KO neurons (Fig. 4a, b).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Syt1 cKO mice
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In the paper
“It is notable that only 1 out of 85 screened crystals in the long unit cell form diffracted to 4.1 Å at APS, while 61 out of ~ 72 long unit cell crystals diffracted to at least 3.5 Å at LCLS.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > The LCLS XFEL produced superior electron density maps
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In the paper
“The long unit cell form occurred much more frequently (about 80%).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > XFEL data collection and processing
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In the paper
“Note that the primary interfaces have relatively low B-factors, similar to the majority of the structure, while parts of the C2A and C2B domains involved in the secondary and tertiary interfaces have higher B-factors”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Extended Data
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In the paper
“Interestingly, while the short unit cell crystal form produced a limiting resolution of 3.6 Å at APS NE-CAT, the density maps are substantially less well defined for sidechains compared to the LCLS data set (compare Extended Data Figs. 2c–f and Figs. 3b, c).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > The LCLS XFEL produced superior electron density maps
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In the paper
“Of the 148 crystals used in the experiment, 113 crystals produced 578 images that could be processed; the other crystals did not diffract or showed multiple lattices.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > XFEL data collection and processing
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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In the paper
“The primary interface is very similar in both crystal forms: the RMSD for the primary interface between both crystal forms is 0.38 Å (bright-orange) and 0.42 Å (white) for complex I and complex II, respectively”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Extended Data
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In the paper
“Using a reverse vapor-diffusion method led to thicker crystal plates (Extended Data Fig. 1e), and eventually produced Bragg peaks past 4 Å resolution.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Crystallization of the Ca2+-bound Syt1-SNARE complex
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In the paper
“Furthermore, the entire crystal was damaged when exposed at room temperature, requiring many more crystals and much more time to collect a complete diffraction dataset.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > XFEL data collection and processing
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In the paper
“The final model consists of four Syt1 C2B molecules in the asymmetric unit.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Structure determination
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In the paper
“This morphological change of the plasma membrane juxtaposes the membranes closer than the critical distance (0.9 nm) to promote stalk formation48 (Fig. 5d), and subsequently leads to fusion pore opening (Fig. 5e).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Model of Syt1 mediated Ca2+ triggering
What the sources say
- Not checked — no full text of the sourcecites [48] Aeffner, S., Reusch, T., Weinhausen, B. & Salditt, T. Energetics of stalk intermediates in membrane fusion are controlled by lipid composition. Proc. Natl Acad. Sci. USA 109, E1609–E1618 (2012) source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- The authors state this as an assumption: Prior to Ca2+ influx, there is a membrane juxtaposed, hemifusion-free state, the likely starting state for fast Ca2+ triggered fusion, and a partially folded trans-SNARE complex.
- The authors state this as an assumption: The Syt1 C2B-SNARE unit can assemble in the pre-Ca2+ state.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Together, these observations support the notion that the primary Syt1-SNARE interface is critical for the role of Syt1 as a Ca2+ sensor of evoked release, but that this Syt1-SNARE interface is not required for spontaneous release in neurons, consistent with the differential effect of Syt1 mutations on spontaneous and evoked release11–13.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Evoked release requires primary interface
What the sources say
- Not checked — no full text of the sourcecites [11] Yoshihara, M. & Littleton, J. T. Synaptotagmin I functions as a calcium sensor to synchronize neurotransmitter release. Neuron 36, 897–908 (2002) source
- Not checked — no full text of the sourcecites [12] Maximov, A. & Südhof, T. C. Autonomous function of synaptotagmin 1 in triggering synchronous release independent of asynchronous release. Neuron 48, 547–554 (2005) source
- Not checked — no full text of the sourcecites [13] Kochubey, O. & Schneggenburger, R. Synaptotagmin increases the dynamic range of synapses by driving Ca2+-evoked release and by clamping a near-linear remaining Ca2+ sensor. Neuron 69, 736–748 (2011) source
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In the paper
“All of these interactions may be anchored by the primary interface, which is the most stable and extensive contact site.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Model of Syt1 mediated Ca2+ triggering
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“Tests of this interface by mutagenesis suggest that it is essential for Ca2+-triggered neurotransmitter release in neuronal synapses and for Ca2+-triggered vesicle fusion in a reconstituted system.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Abstract
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In the paper
“In contrast, other synaptotagmin isoforms not involved in fast synchronous release exhibit sequence variations and differences in the electrostatic potential maps in both regions (Extended Data Figs. 6a, b), suggesting that the primary interface may be an interaction that is specific for fast synchronous release.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > The conserved primary interface
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In the paper
“This entire Syt1-SNARE assembly would thus be poised to confer cooperativity upon Ca2+-triggering on a sub-millisecond timescale.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Model of Syt1 mediated Ca2+ triggering
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Probably not a substantial claim.
- The authors state this as an assumption: Prior to Ca2+ influx, there is a membrane juxtaposed, hemifusion-free state, the likely starting state for fast Ca2+ triggered fusion, and a partially folded trans-SNARE complex.
- The authors state this as an assumption: The Syt1 C2B-SNARE unit can assemble in the pre-Ca2+ state.
In the paper
“For example, increased ensemble lipid mixing was observed upon addition of the soluble Syt1 C2AB fragment and Ca2+ (ref. 21).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Single vesicle-vesicle content-mixing assay
What the sources say
- Not checked — no full text of the sourcecites [21] Martens, S., Kozlov, M. M. & McMahon, H. T. How synaptotagmin promotes membrane fusion. Science 316, 1205–1208 (2007) source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In fact, only a lack of available XFEL beamtime prevented us from collecting a complete diffraction dataset beyond 3.5 Å.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > The LCLS XFEL produced superior electron density maps
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“As described previously81, the presence and purity of reconstituted proteins was confirmed by SDS-PAGE of the vesicle preparations, and the directionality of the membrane proteins (facing outward) was assessed by chymotrypsin digestion followed by SDS-PAGE.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Protein reconstitution for single vesicle-vesicle fusion experiments
What the sources say
- Not checked — no full text of the sourcecites [81] Kyoung, M. et al. In vitro system capable of differentiating fast Ca2+-triggered content mixing from lipid exchange for mechanistic studies of neurotransmitter release. Proc. Natl Acad. Sci. USA 108, E304–E313 (2011) source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“as a consequence, the interactions between residues R281, K288, R398 of the Syt1 C2B (I′) domain and residues E224, E228 of syntaxin-1A are slightly changed by this rotation.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Extended Data
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The best constructs resulted in a Syt1-SNARE complex that eluted in a mono-disperse peak in the final size-exclusion chromatography step, and that remained stable in SDS-PAGE without boiling, a hallmark for neuronal SNARE complex formation (Extended Data Fig. 1b).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Strategy for crystallization of the Syt1-SNARE complex
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, the role of these residues was unclear in the absence of structural information, which now reveals that they are part of a larger interface between Syt1 and the SNARE complex.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Design of mutations to disrupt the primary interface
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The role of the region II interacting residues was unclear in the absence of structural information.
In the paper
“However, in retrospect, this result was probably caused by an effect on vesicle association since multivalent binding of the soluble Syt1 C2AB fragment can induce vesicle clustering19.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Single vesicle-vesicle content-mixing assay
What the sources say
- Not checked — no full text of the sourcecites [19] Araç, D. et al. Close membrane-membrane proximity induced by Ca2+-dependent multivalent binding of synaptotagmin-1 to phospholipids. Nature Struct. Mol. Biol. 13, 209–217 (2006) source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These maps, superior to those of the short unit cell data crystal structure collected at the APS NE-CAT microfocus synchrotron beamline at comparable limiting resolution (Extended Data Figs. 3b, c), enabled us to better investigate the binding interfaces between Syt1 and the SNARE complex, and was thus essential for the structural portion of our study.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > The LCLS XFEL produced superior electron density maps
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, the LCLS diffraction data set proved notably superior to the particular synchrotron-derived datasets that we collected in terms of limiting resolution and quality of the electron density maps, and was thus essential for more accurately determining side chain positions.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > The LCLS XFEL produced superior electron density maps
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taking into account the smaller number of molecules in the asymmetric unit of the short unit cell crystal form (2 Syt1 and 1 SNARE complex compared 3 Syt1 and 2 SNARE complexes), there are still fewer Ca2+ sites that were observed in maps derived from the data set collected at APS, suggesting that Ca2+-binding sites have been affected by radiation damage.”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > The LCLS XFEL produced superior electron density maps
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“A subset of the interacting residues of region II were suggested to be functionally important in previous studies: Syt1 R398, R399 (refs. 35,36,78), and SNAP-25 D51, E52, E55 (refs. 27,79,80).”
§ Architecture of the Synaptotagmin-SNARE Machinery for Neuronal Exocytosis > Methods > Design of mutations to disrupt the primary interface
What the sources say
- Not matchedcites refs. 35,36,78
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites refs. 27,79,80
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Not matched
The authors state this as an assumption.
Prior to Ca2+ influx, there is a membrane juxtaposed, hemifusion-free state, the likely starting state for fast Ca2+ triggered fusion, and a partially folded trans-SNARE complex.
“Prior to Ca2+ influx, we assume a membrane juxtaposed, hemifusion-free state (Fig. 5c), the likely starting state for fast Ca2+ triggered fusion37, and a partially folded trans-SNARE complex46.”
The authors state this as an assumption.
The Syt1 C2B-SNARE unit can assemble in the pre-Ca2+ state.
“We assume that the Syt1 C2B-SNARE unit can assemble in this state since the primary interface involves residues within the folded region of the trans-SNARE complex.”
The paper relies on this without support.
The atomic-resolution structure of the complex between Syt1 and the neuronal SNARE complex has been elusive.
“However, the atomic-resolution structure of the complex between Syt1 and the neuronal SNARE complex (referred to as Syt1-SNARE complex) has been elusive.”
The paper relies on this without support.
The molecular basis and the significance of the interaction between Syt1 and the SNARE complex remain unknown.
“but the molecular basis and the significance of the interaction between Syt1 and the SNARE complex remain unknown.”
The paper relies on this without support.
It is unknown how Syt1 and neuronal SNARE proteins cooperate to trigger synaptic vesicle fusion.
“However, it is unknown how they cooperate to trigger synaptic vesicle fusion.”
The paper relies on this without support.
It is unknown at the atomic level of detail how these factors cooperate with SNAREs to promote synaptic transmission.
“but it is unknown at the atomic level of detail how these factors cooperate with SNAREs to promote synaptic transmission.”
The paper relies on this without support.
Interactions in region I have not been implicated in any previous studies.
“Moreover, interactions in region I (Fig. 2a) have not been implicated in any previous studies.”
The paper relies on this without support.
The role of the region II interacting residues was unclear in the absence of structural information.
“However, the role of these residues was unclear in the absence of structural information, which now reveals that they are part of a larger interface between Syt1 and the SNARE complex.”
Citations
Cites
UCSF Chimera—A visualization system for exploratory research and analysis
Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004) · Journal of Computational Chemistry · doi:10.1002/jcc.20084 · Cited by 45,882
Coot : model-building tools for molecular graphics
Emsley, P., & Cowtan, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904019158 · Cited by 30,571
Phaser crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612
Kabsch, W. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909047337 · Cited by 16,463
Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination
Brünger, A. T., Adams, P. D., Clore, G. M., DeLano, W. L., Gros, P., Grosse‐Kunstleve, R. W., Jiang, J., Kuszewski, J. J., Nilges, M., Pannu, N., et al. (1998) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444998003254 · Cited by 15,723
MolProbity : all-atom structure validation for macromolecular crystallography
Chen, V. B., Arendall, W. B., Headd, J. J., Keedy, D. A., Immormino, R. M., Kapral, G. J., Murray, L. W., Richardson, J. S., & Richardson, D. C. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909042073 · Cited by 14,115
Overview of the CCP 4 suite and current developments
Winn, M. D., Ballard, C. C., Cowtan, K. D., Dodson, E. J., Emsley, P., Evans, P. R., Keegan, R. M., Krissinel, E. B., Leslie, A. G. W., McCoy, A., et al. (2011) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910045749 · Cited by 12,353
Inference of Macromolecular Assemblies from Crystalline State
Krissinel, E., & Henrick, K. (2007) · Journal of Molecular Biology · doi:10.1016/j.jmb.2007.05.022 · Cited by 10,007
Protein production by auto-induction in high-density shaking cultures
Studier, F. W. (2005) · Protein Expression and Purification · doi:10.1016/j.pep.2005.01.016 · Cited by 5,949
PHENIX : building new software for automated crystallographic structure determination
Adams, P. D., Grosse-Kunstleve, R. W., Hung, L.-W., Ioerger, T. R., McCoy, A. J., Moriarty, N. W., Read, R. J., Sacchettini, J. C., Sauter, N. K., & Terwilliger, T. C. (2002) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444902016657 · Cited by 4,361
Self-citation
Cited by
Sorted by citations
Linac Coherent Light Source: The first five years
Bostedt, C., Boutet, S., Fritz, D., Huang, Z., Lee, H. J., Lemke, H. T., Robert, A., Schlotter, W. F., Turner, J. J., & Williams, G. J. (2016) · Reviews of Modern Physics · doi:10.1103/revmodphys.88.015007 · Cited by 628
Self-citationThe mechanisms and functions of synaptic facilitation.
Jackman, S. L., & Regehr, W. G. (2017) · Neuron · doi:10.1016/j.neuron.2017.02.047 · Cited by 489
Structure of photosystem II and substrate binding at room temperature
Young, I. D., Ibrahim, M., Chatterjee, R., Gul, S., Fuller, F. D., Koroidov, S., Brewster, A. S., Tran, R., Alonso‐Mori, R., Kröll, T., et al. (2016) · Nature · doi:10.1038/nature20161 · Cited by 389
Self-citationThe primed SNARE–complexin–synaptotagmin complex for neuronal exocytosis
Zhou, Q., Zhou, P., Wang, A. L., Wu, D., Zhao, M., Südhof, T. C., & Brünger, A. T. (2017) · Nature · doi:10.1038/nature23484 · Cited by 293
Self-citationThe Multifaceted Role of SNARE Proteins in Membrane Fusion
Han, J., Pluháčková, K., & Böckmann, R. A. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00005 · Cited by 286
“The zippering of the TMDs of t- and vSNARE proteins facilitated lipid mixing and pore nucleation and the presence of the heterodimer at the pore rim was suggested to obstruct pore resealing (Wu et al., 2016).”
Background
Metadata
- Authors
- Zhou, Q., Lai, Y., Bacaj, T., Zhao, M., Lyubimov, A. Y., Uervirojnangkoorn, M., Zeldin, O. B., Brewster, A. S., Sauter, N. K., Cohen, A. E., Soltis, S. M., Alonso-Mori, R., Chollet, M., Lemke, H. T., Pfuetzner, R. A., Choi, U. B., Weis, W. I., Diao, J., Südhof, T. C., & Brunger, A. T.
- Affiliations
- Howard Hughes Medical Institute (US)
- Lawrence Berkeley National Laboratory (US)
- SLAC National Accelerator Laboratory (US)
- Stanford University (US)
- Corresponding author
- Südhof, Thomas C.
- ORCID
- Venue
- Nature
- Published
- 2015-08-17
- Volume
- 525
- Issue
- 7567
- Pages
- 62-67
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4607316
- OpenAlex
- W2128007435
- Semantic Scholar
- 6268e2754a251c4960dbe44d56fb172dcf37831e
- Cited by
- 348
- References
- 95
- Citations by year
- 2026: 20 · 2025: 20 · 2024: 48 · 2023: 27 · 2022: 33 · 2021: 23 · 2020: 29 · 2019: 27 · 2018: 37 · 2017: 42 · 2016: 36 · 2015: 6
- FWCI
- 18.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.osti.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Department of Energy (76SF00515, DE–AC02–76SF00515, P41 GM103403, P41GM103393, AC02‐76SF00515, DE-AC02-)
- National Institutes of Health (3p41gm103403-15s1, 8p41gm103393-33, DE-AC02-76SF00515, R37 MH63105, P41 GM103403, P41 GM103393, MH086403, GM103403, GM102520, GM095887)
- Office of Science (AC02-76SF00515, P41GM103393, DE-AC02-76SF0051 5, DE-AC02, 76SF00515)
- National Institute of Mental Health (R37 MH063105, MH086403, P50 MH086403, R37MH63105)
- National Institute of General Medical Sciences (R01-GM095887, R01 GM102520, P41-GM-103393, R01 GM077071, GM095887, DE-AC02-76SF00515, P41GM103403, GM102520, GM-103403)
- Basic Energy Sciences (DE-AC02, P41GM103393, 76SF00515, AC02-76SF00515, GM103403, DE-AC-02-76SF00515)
- Biological and Environmental Research (P41 GM103393, DE- AC0276SF00515)
- SLAC National Accelerator Laboratory (DEAC02−76SF00515, AC02‐76SF00515, P41GM103393)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Keywords
- synaptotagmin-1, synaptic vesicle fusion, neurotransmitter release, calcium-triggered exocytosis, protein complex crystal structure, hippocampal synapses, membrane remodeling
- MeSH terms
- Animals, Binding Sites, Calcium, Cell Membrane, Electrons, Exocytosis, Hippocampus, Lasers, Magnesium, Membrane Fusion, Models, Biological, Models, Molecular, Mutation, Synaptic Transmission, Neurons, Synaptic Vesicles, Crystallography, X-Ray, SNARE Proteins, Synaptotagmins, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-12, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-12 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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