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Cited by 76Cellular transport and secretionNeuroscience and Neuropharmacology ResearchLipid Membrane Structure and Behavior

Ca2+-dependent release of synaptotagmin-1 from the SNARE complex on phosphatidylinositol 4,5-bisphosphate-containing membranes

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Voleti, Rashmi, Jaczynska, Klaudia, Rizo, Josep·2020·eLife
DOI 10.7554/elife.57154PMC PMC7498268
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Abstract

The Ca 2+ sensor synaptotagmin-1 and the SNARE complex cooperate to trigger neurotransmitter release. Structural studies elucidated three distinct synaptotagmin-1-SNARE complex binding modes involving ‘polybasic’, ‘primary’ and ‘tripartite’ interfaces of synaptotagmin-1. We investigated these interactions using NMR and fluorescence spectroscopy. Synaptotagmin-1 binds to the SNARE complex through the polybasic and primary interfaces in solution. Ca 2+ -free synaptotagmin-1 binds to SNARE complexes anchored on PIP 2 -containing nanodiscs. R398Q/R399Q and E295A/Y338W mutations at the primary interface, which strongly impair neurotransmitter release, disrupt and enhance synaptotagmin-1-SNARE complex binding, respectively. Ca 2+ induces tight binding of synaptotagmin-1 to PIP 2 -containing nanodiscs, disrupting synaptotagmin-1-SNARE interactions. Specific effects of mutations in the polybasic region on Ca 2+ -dependent synaptotagmin-1-PIP 2 -membrane interactions correlate with their effects on release. Our data suggest that synaptotagmin-1 binds to the SNARE complex through the primary interface and that Ca 2+ releases this interaction, inducing PIP 2 /membrane binding and allowing cooperation between synaptotagmin-1 and the SNAREs in membrane fusion to trigger release.

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  • Prior to calcium influx, Syt-1 is bound to the SNARE complex, inhibiting neurotransmitter release; calcium triggering requires rearrangement of the primary interface involving dissociation of region I while region II remains bound.

    “Prior to calcium influx, Syt-1 is already bound to the SNARE complex, a state that inhibits the release of neurotransmitters. Calcium triggering then requires a rearrangement of the primary interface involving the dissociation of region I, while region II remains bound to the SNARE complex.”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [26]

    The Discussion (Figure 10 model; page unavailable) proposes that Syt1 binds the SNARE complex before Ca2+ influx in an assembly that inhibits release. But it proposes that Ca2+ releases the Syt1–SNARE interaction, not that region II remains bound; the Results identify region II as part of the primary interface (page unavailable). (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Voleti, R., Jaczynska, K., & Rizo, J.
Affiliations
The University of Texas Southwestern Medical Center (US)
Corresponding author
Rizo, Josep
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2020-08-18
Volume
9
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.57154
PMC
PMC7498268
OpenAlex
W3060922084
Cited by
76
References
3
Citations by year
2026: 5 · 2025: 8 · 2024: 16 · 2023: 18 · 2022: 13 · 2021: 15 · 2020: 1
FWCI
5.86
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute of Neurological Disorders and Stroke (R35 NS097333)
  • Welch Foundation (I-1304)
  • Howard Hughes Medical Institute
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 › Lipid Membrane Structure and Behavior
Keywords
synaptotagmin-1, SNARE complex, calcium-dependent release, phosphatidylinositol 4,5-bisphosphate, neurotransmitter release, polybasic region, membrane fusion, nanodiscs, synaptic vesicle exocytosis
MeSH terms
Animals, Calcium, Cell Membrane, Synaptic Transmission, Phosphatidylinositol 4,5-Diphosphate, SNARE Proteins, Synaptotagmin I, Rats

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