Microtubule lattice spacing governs cohesive envelope formation of tau family proteins
Open accessPublished version of a preprint
Abstract
Tau is an intrinsically disordered microtubule-associated protein (MAP) implicated in neurodegenerative disease. On microtubules, tau molecules segregate into two kinetically distinct phases, consisting of either independently diffusing molecules or interacting molecules that form cohesive 'envelopes' around microtubules. Envelopes differentially regulate lattice accessibility for other MAPs, but the mechanism of envelope formation remains unclear. Here we find that tau envelopes form cooperatively, locally altering the spacing of tubulin dimers within the microtubule lattice. Envelope formation compacted the underlying lattice, whereas lattice extension induced tau envelope disassembly. Investigating other members of the tau family, we find that MAP2 similarly forms envelopes governed by lattice spacing, whereas MAP4 cannot. Envelopes differentially biased motor protein movement, suggesting that tau family members could spatially divide the microtubule surface into functionally distinct regions. We conclude that the interdependent allostery between lattice spacing and cooperative envelope formation provides the molecular basis for spatial regulation of microtubule-based processes by tau and MAP2.
AI snapshot
Written from the paper’s full text.
TL;DR
Tau and MAP2c form cooperative, cohesive envelopes on microtubules by locally compacting the tubulin lattice, whereas MAP4 does not. This lattice-spacing-dependent mechanism can spatially regulate motor proteins and is revealed in cells by taxol-induced lattice extension causing tau envelope disassembly.
Key findings
- Tau envelope formation is cooperative, with a Hill coefficient of 1.9 ± 0.7, and preferentially occurs on compacted GDP-lattice microtubules: coverage rate was 1.6 ± 1.3 μm/s on GDP lattices versus 23.0 ± 12.8 nm/s on taxol lattices, with no envelope formation on GMPCPP lattices.
- Tau envelopes compact the underlying lattice by 3.2 ± 1.0% and reduce SiR-tubulin intensity within enveloped regions by 21.7 ± 12.9%; cryo-EM showed ~1 Å compaction between tubulin monomers for both tau and MAP2c, while MAP4 caused no measurable compaction.
- MAP2c behaves like tau, forming envelopes on taxol-lattice but not GMPCPP-lattice microtubules, and co-enriches with tau in shared envelopes; MAP4 does not form envelopes, is excluded from tau/MAP2c envelopes, and remains uniformly bound.
- Mechanical lattice extension destabilizes tau envelopes: hydrodynamic bending caused ~50% tau density drop in curved regions, and optical-trap stretching increased envelope disassembly rate 2-fold. In U-2 OS cells, taxol caused tau dissociation from microtubules in all cells observed, while MAP4 remained.
Methods
- In vitro TIRF microscopy with purified porcine brain tubulin and fluorescently labeled full-length tau, MAP2c, MAP4, kinesin-1, DDH, and KIF1A, using taxol-stabilized, GMPCPP-stabilized, and GMPCPP-capped GDP-lattice microtubules; assays included FRAP, speckle tracking, SiR-tubulin binding, 1,6-hexanediol treatment, and optical tweezers.
- Cryo-EM of taxol-stabilized microtubules incubated with tau, MAP2c, or MAP4 to measure longitudinal lattice spacing via the 4 nm Js reflection.
- Live-cell TIRF imaging of U-2 OS cells expressing eGFP-tau or eGFP-MAP4, with taxol or DMSO treatment and quantification by coefficient of variation and envelope fission/disassembly analysis.
Limitations
- The paper does not state a dedicated limitations section. Evident from the text: most mechanistic work uses in vitro reconstitution with taxol- or GMPCPP-manipulated microtubules and purified proteins, which may not fully reproduce native cellular lattices.
- Live-cell experiments use U-2 OS cells with overexpression of eGFP-tau or eGFP-MAP4 rather than neurons, and taxol is used to artificially extend lattices.
- Cryo-EM used high MAP concentrations (27 μM tau, 28 μM MAP2c, 34 μM MAP4), and tau showed a bimodal lattice-spacing distribution, suggesting incomplete envelope coverage under those conditions.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
Statistics
Claims the paper makes
31 of 32 cited sources checked · 21 supported · 0 flagged · accuracy not yet measured
- Interpretationcitation
The extent of tau-induced lattice compaction (3.2 ± 1.0%) is similar to the length difference between GTP- and GDP-bound tubulin dimers estimated previously by cryo-EM to be 2.4%.
“The extent of the compaction is similar to the length difference between GTP- and GDP-bound tubulin dimers estimated previously by cryo-EM to be 2.4%1”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [1] Alushin, G. M. et al. High-resolution microtubule structures reveal the structural transitions in αβ-tubulin upon GTP hydrolysis. Cell 157, 1117–1129 (2014). source
- Findingcitation
Tau was highly co-enriched within tau envelopes.
“As expected9, tau was highly co-enriched within tau envelopes”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [9] Tan, R. et al. Microtubules gate tau condensation to spatially regulate microtubule functions. Nat. Cell Biol. 21, 1078–1085 (2019). source
- Premisecitation
Tau envelopes can be detected by their occlusion of kinesin-1.
“However, tau envelopes can be detected by their effect on kinesin-1, which is occluded from the envelopes28.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [28] Siahaan, V. et al. Kinetically distinct phases of tau on microtubules regulate kinesin motors and severing enzymes. Nat. Cell Biol. 21, 1086–1092 (2019). source
- Findingown data
After adding 0.01 μM taxol to U-2 OS cells, tau dissociated from microtubules in all cells, as quantified by a decrease in the coefficient of variation of the tau signal.
“We added 0.01 μM taxol to the medium and imaged the cells for 10 minutes while monitoring the tau density on microtubules initially fully covered by eGFP-tau. In line with our in vitro observations, and previous in vivo evidence33,35, we observed that in all cells tau dissociated from the microtubules (Fig. 4a, Supplementary Movie 9) as quantified by the decrease in the coefficient of variation of”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [33] Samsonov, A., Yu, J.-Z., Rasenick, M. & Popov, S. V. Tau interaction with microtubules in vivo. J. Cell Sci. 117, 6129–6141 (2004). source
- cites [35] Ettinger, A., van Haren, J., Ribeiro, S. A. & Wittmann, T. Doublecortin is excluded from growing microtubule ends and recognizes the GDP-microtubule lattice. Curr. Biol. 26, 1549–1555 (2016). source
- Findingcitation
In the remaining 6% of cells, exhibiting weak eGFP-tau expression, tau only localized to the microtubule bends.
“In the remaining 6% of cells, exhibiting weak eGFP-tau expression, tau only localized to the microtubule bends, as described previously33,34.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [33] Samsonov, A., Yu, J.-Z., Rasenick, M. & Popov, S. V. Tau interaction with microtubules in vivo. J. Cell Sci. 117, 6129–6141 (2004). source
In “Binding of tau to individual MTs depends on their curvature” (page unavailable), the paper reports more GFP-tau at highly curved regions. It also reports GFP-tau labeling on relatively straight microtubules, so localization was not limited to bends. The passages do not support the figure of 6% of cells with weak expression. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [34] Balabanian, L., Berger, C. L. & Hendricks, A. G. Acetylated microtubules are preferentially bundled leading to enhanced kinesin-1 motility. Biophys. J. 113, 1551–1560 (2017). source
The section “Tau is enriched on curved microtubule segments” (page unavailable) reports preferential tau localization at bends in extracted cytoskeletal networks and notes that localization on curved microtubules has been observed in living cells. It does not report a 6% subgroup, weak eGFP-tau expression, or localization only at bends. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
If tau were bound non-cooperatively, tau would unbind uniformly along the microtubule length, as observed for non-cooperatively bound tau in vitro.
“If tau would have been bound non-cooperatively, we would expect tau to unbind from the microtubules uniformly along the microtubule length, as observed for non-cooperatively bound tau in vitro28.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [28] Siahaan, V. et al. Kinetically distinct phases of tau on microtubules regulate kinesin motors and severing enzymes. Nat. Cell Biol. 21, 1086–1092 (2019). source
- Findingown data
During taxol-driven extension of the native compacted microtubule lattice, tau signal disappeared from microtubules in patterns resembling disassembly of tau envelopes in vitro.
“we found that the tau signal disappeared from the microtubules in patterns that resembled the disassembly of tau envelopes in vitro9,28.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [9] Tan, R. et al. Microtubules gate tau condensation to spatially regulate microtubule functions. Nat. Cell Biol. 21, 1078–1085 (2019). source
- cites [28] Siahaan, V. et al. Kinetically distinct phases of tau on microtubules regulate kinesin motors and severing enzymes. Nat. Cell Biol. 21, 1086–1092 (2019). source
- Findingown data
Addition of MAP4 did not result in measurable compaction within the tubulin lattice.
“In contrast, addition of MAP4 did not result in measurable compaction within the tubulin lattice”
Quote in the paperSubstantial claim - Findingown data
No compaction was detected in a control experiment when buffer was exchanged but no tau was added.
“No compaction was detected in a control experiment when the buffer was exchanged but no tau was added”
Quote in the paperSubstantial claim - Findingown data
TMR-MAP4 molecules remained diffusive regardless of concentration.
“In contrast, TMR-MAP4 molecules remained diffusive regardless of the concentration”
Quote in the paperSubstantial claim - Findingown data
1,6-Hexanediol had no effect on the binding of MAP4 to microtubules.
“In contrast, 1,6-HD had no effect on the binding of MAP4 to microtubules”
Quote in the paperSubstantial claim - Findingown data
MAP2c molecules turned over ~4-fold faster outside versus inside envelope boundaries.
“MAP2c molecules turned over ~4-fold faster when they resided outside versus inside envelope boundaries”
Quote in the paperSubstantial claim - Findingown data
When all three MAPs were co-mixed at equimolar concentrations, tau and MAP2c strongly co-segregated into envelopes that excluded MAP4 into surrounding regions.
“we co-mixed all three MAPs at equimolar concentrations and observed strong co-segregation of tau and MAP2c into envelopes that excluded MAP4 into the surrounding regions”
Quote in the paperSubstantial claim - Findingown data
During hydrodynamic flow, tau density in highly curved regions dropped by approximately 50%, indicating a fissure in the envelope.
“We found that, during the flow period, both in presence and absence of taxol, the tau density in the highly curved regions dropped by approximately 50% (Fig. 2b), indicating a fissure in the envelope.”
Quote in the paperSubstantial claim - Findingown data
The disassembly rate of tau envelopes increased 2-fold when the microtubule lattice was stretched by an external force.
“We found that the disassembly rate of tau envelopes increased 2-fold when the microtubule lattice was stretched by an external force.”
Quote in the paperSubstantial claim - Findingown data
MAP2c envelopes were not dissolved by the 1,6-hexanediol isomer 2,5-hexanediol.
“MAP2c envelopes were not dissolved by the 1,6-HD isomer 2,5-hexanediol”
Quote in the paperSubstantial claim - Findingown data
Both tau and MAP2c binding resulted in ~1Å compaction between tubulin monomers in cryo-EM.
“we found that both tau and MAP2c binding resulted in ~1Å compaction between tubulin monomers”
Quote in the paperSubstantial claim - Findingown data
During tau envelope growth, microtubules often straighten.
“During envelope growth we often observed straightening of microtubules (Fig. 1c, Supplementary Movie 1)”
Quote in the paperNot a substantial claim - Findingown data
MAP4 was largely excluded from tau envelopes.
“By contrast, MAP4 was largely excluded from tau envelopes”
Quote in the paperSubstantial claim - Findingown data
The diffusive behavior of TMR-MAP2c outside of GFP-MAP2c envelopes did not change with increasing concentrations of GFP-MAP2c.
“The diffusive behavior of TMR-MAP2c outside of the GFP-MAP2c envelopes did not change with increasing concentrations of GFP-MAP2c.”
Quote in the paperSubstantial claim - Findingown data
No tau envelope formation was observed on GMPCPP-lattice microtubules.
“no envelope formation was observed on GMPCPP-lattice microtubules (Fig. 1d, Supplementary Fig. 1a–d).”
Quote in the paperSubstantial claim - Findingown data
SiR-tubulin intensity within tau envelope regions decreased by 21.7 ± 12.9% compared to outside.
“Comparison of the SiR-tubulin intensity within or outside the tau envelope regions (Fig. 1i,j, Supplementary Movie 4) revealed a decrease of 21.7 ± 12.9% (mean ± s.d.) within the enveloped regions.”
Quote in the paperSubstantial claim - Findingown data
At picomolar concentrations, both MAP2c and MAP4 molecules showed predominantly diffusive interactions with microtubules.
“At picomolar concentrations, both MAP2c and MAP4 molecules showed predominantly diffusive interactions with microtubules”
Quote in the paperSubstantial claim - Findingown data
The intensity of MAP4 was identical on either type of lattice.
“The intensity of MAP4 was identical on either type of lattice (Fig. 3b), further suggesting that MAP4 cannot form envelopes.”
Quote in the paperSubstantial claim - Findingown data
The rate at which tau envelopes cover GDP-lattice microtubules (1.6 ± 1.3 μm/s) is more than an order of magnitude faster than the coverage rate on taxol-lattice microtubules (23.0 ± 12.8 nm/s).
“We observed that the rate with which tau envelopes covered the GDP-lattice microtubules (1.6 ± 1.3 μm/s; mean ± s.d) was more than an order of magnitude faster than the coverage rate on taxol-lattice microtubules (23.0 ± 12.8 nm/s; mean ± s.d)”
Quote in the paperSubstantial claim - Findingown data
Addition of MAP2c caused a more complete compaction, to a level consistent with the compacted tau lattice.
“Addition of MAP2c caused a more complete compaction, to a level consistent with the compacted tau lattice”
Quote in the paperSubstantial claim - Findingown data
In cells treated with taxol, envelope-like disassembly was always observed, rather than uniform tau unbinding.
“However, in cells treated with taxol we always observed envelope-like disassembly, rather than uniform tau unbinding.”
Quote in the paperSubstantial claim - Findingown data
At low concentrations of MAP2c, occasional pausing of DDH complexes at the envelope boundary was observed.
“At low concentrations of MAP2c, where envelope boundaries are visible, we observed occasional pausing of DDH complexes at the envelope boundary”
Quote in the paperNot a substantial claim - Findingown data
KIF1A motors bound and moved along microtubules in the absence and presence of low concentrations of MAP2c and MAP4.
“KIF1A motors bound and moved along microtubules in the absence and presence of low concentrations of MAP2c and MAP4”
Quote in the paperSubstantial claim - Findingown data
The distinct regions of tau signal formed by fissures then disassembled from their boundaries until they disappeared, similar to tau envelope disassembly in vitro.
“The distinct regions of tau signal formed by these fissures then disassembled from their boundaries until they disappeared, similar to tau envelope disassembly in vitro”
Quote in the paperSubstantial claim - Findingown data
Individual MAP4 molecules located within tau/MAP2c envelopes remained static.
“Further, individual MAP4 molecules located within the tau/MAP2c envelopes remained static”
Quote in the paperSubstantial claim - Findingown data
Neither MAP2c nor MAP4 strongly affected the average velocity (including pauses) of DDH motors.
“Neither MAP strongly affected the average velocity (including pauses) of these motors”
Quote in the paperNot a substantial claim - Findingown data
There was a strong spatial effect of MAP2c on KIF1A.
“In contrast to DDH, we observed a strong spatial effect of MAP2c on KIF1A”
Quote in the paperSubstantial claim - Findingown data
DDH complexes bound and moved processively along microtubules in the absence and presence of both MAP2c and MAP4.
“In our assays, DDH complexes bound and moved processively along microtubules in the absence and presence of both MAP2c and MAP4”
Quote in the paperSubstantial claim - Findingown data
In U-2 OS cells expressing eGFP-MAP4, MAP4 remained on microtubules after either DMSO or taxol treatment, as quantified by unchanged coefficient of variation.
“we found that MAP4 remained on the microtubules after either treatment with DMSO or taxol (Fig. 4c, Supplementary Movie 11,12), as quantified by the unchanged coefficient of variation”
Quote in the paperSubstantial claim - Interpretationown data
Cooperative tau envelopes preferably form on compacted GDP-lattice microtubules.
“These results demonstrate that cooperative tau envelopes preferably form on compacted GDP-lattice microtubules.”
Quote in the paperSubstantial claim - Interpretationown data
Permanent extension of the microtubule lattice prevents tau envelope formation.
“Permanent extension of the microtubule lattice thus prevents envelope formation”
Quote in the paperSubstantial claim - Interpretationown data
A localized structural shift to the compacted GDP-tubulin microtubule lattice induces cooperative formation of tau envelopes.
“Combined, these experiments show that a localized structural shift to the compacted GDP-tubulin microtubule lattice induces cooperative formation of tau envelopes.”
Quote in the paperSubstantial claim - Interpretationown data
Tau envelopes shift tubulin from its extended GTP-like into its compacted GDP-conformation.
“suggesting that tau envelopes shift tubulin from its extended GTP-like into its compacted GDP-conformation.”
Quote in the paperSubstantial claim - Interpretationown data
Microtubule lattice spacing might regulate tau envelope formation.
“suggesting that the microtubule lattice spacing might regulate the envelope formation.”
Quote in the paperSubstantial claim - Interpretationown data
Transient local extension of the lattice by mechanical means destabilizes tau envelopes.
“These results demonstrate that transient local extension of the lattice by mechanical means destabilizes tau envelopes.”
Quote in the paperSubstantial claim - Interpretationreasoning
Tau functions in living cells may be mechanosensitive.
“suggesting that tau functions in living cells may be mechanosensitive.”
Quote in the paperSubstantial claim - Interpretationown data
Cooperative binding of tau influences microtubule structure.
“suggesting that cooperative binding of tau influences the microtubule structure.”
Quote in the paperSubstantial claim - Interpretationown data
Tau envelope formation induces a reversible compaction of taxol-extended tubulin.
“Tau envelope formation induces a reversible compaction of taxol-extended tubulin.”
Quote in the paperSubstantial claim - Interpretationown data
The 1,6-hexanediol experiments suggest that phase separation of tau and MAP2 on the microtubule surface might contribute to cooperative envelope formation.
“Additionally, our 1,6-hexanediol experiments suggest that phase separation of tau and MAP2 on the microtubule surface might contribute to cooperative envelope formation.”
Quote in the paperNot a substantial claim - Interpretationown data
Tau binding to the compressed lattice on the inner side of microtubule bends explains the occasionally observed enriched tau signal in bends after taxol addition.
“Our results suggest that this is due to tau binding to the compressed lattice on the inner side of the bends.”
Quote in the paperNot a substantial claim - Interpretationcitation
The microtubule lattice in living cells may not exist in a homogenously compacted, GDP state, as previously thought.
“Thus, the microtubule lattice in living cells may not exist in a homogenously compacted, GDP state, as previously thought.”
Quote in the paperSubstantial claim - Interpretationreasoning
The majority of tau in vivo is bound to microtubules cooperatively.
“our results suggest that the majority of tau in vivo is bound to microtubules cooperatively.”
- Also stated in: § Discussion · hedged
“It is presumed that the predominant volume of the microtubule lattice in cells is in the GDP compacted state, suggesting that most of tau in cells is bound to the microtubule in a cooperative manner”
Quote in the paperSubstantial claim- The authors state this as an assumption: The majority of tubulin incorporated into microtubules in vivo, and the predominant volume of the microtubule lattice in cells, is in the compacted GDP state.
- Also stated in: § Discussion · hedged
- Interpretationown data
The ability to both recognize and alter the conformation of the microtubule lattice suggests functional diversification within the tau family.
“suggesting functional diversification within the tau family related to the ability to both recognize and alter the conformation of the microtubule lattice.”
Quote in the paperSubstantial claim - Interpretationown data
The dissociation of tau from microtubules is specific to taxol treatment.
“showing that the dissociation of tau from microtubules is specific to taxol treatment.”
Quote in the paperSubstantial claim - Interpretationreasoning
Native GDP-microtubule lattices in vivo can be fully enclosed by tau envelopes.
“These results suggest that native GDP-microtubule lattices in vivo can be fully enclosed by tau envelopes.”
Quote in the paperSubstantial claim - Interpretationown data
The interdependent allostery between lattice-spacing and cooperative envelope formation provides the molecular basis for spatial regulation of microtubule-based processes by tau and MAP2.
“We conclude that the interdependent allostery between lattice-spacing and cooperative envelope formation provides the molecular basis for spatial regulation of microtubule-based processes by tau and MAP2.”
Quote in the paperSubstantial claim
- May combine two claims. 46
- Classified as probably not a substantial claim. 13
- The quote only partly states this claim. 2
May combine two claims.
PremisecitationTau envelopes form on GDP microtubule lattices but do not form on GMPCPP-stabilized microtubules.
“Previously, we observed that tau envelopes form on GDP microtubule lattices but do not form on microtubules stabilized with GMPCPP9.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [9] Tan, R. et al. Microtubules gate tau condensation to spatially regulate microtubule functions. Nat. Cell Biol. 21, 1078–1085 (2019). source
May combine two claims.
PremisecitationTau molecules inside envelopes do not diffuse but remain stationary.
“since tau molecules inside envelopes do not diffuse, but remain stationary9,28.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [9] Tan, R. et al. Microtubules gate tau condensation to spatially regulate microtubule functions. Nat. Cell Biol. 21, 1078–1085 (2019). source
The passage describing single-molecule behavior says tau becomes statically bound at condensate boundaries, supporting the stationary characterization. But it also reports a nonzero diffusion coefficient within condensates (4×10−4 µm²/s), so the absolute claim that molecules inside them do not diffuse overstates the result. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [28] Siahaan, V. et al. Kinetically distinct phases of tau on microtubules regulate kinesin motors and severing enzymes. Nat. Cell Biol. 21, 1086–1092 (2019). source
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationThese results are consistent with prior data showing competition between tau and taxol for microtubules.
“These results are consistent with prior data showing competition between tau and taxol for microtubules31.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [31] Kar, S., Fan, J., Smith, M. J., Goedert, M. & Amos, L. A. Repeat motifs of tau bind to the insides of microtubules in the absence of taxol. EMBO J. 22, 70–77 (2003). source
May combine two claims.
Findingown dataThe MAP2c level outside of envelopes was identical to that on GMPCPP-lattice microtubules, similar to tau.
“Quantification of MAP intensity on both types of lattices revealed that the MAP2c level outside of the envelopes was identical to that on GMPCPP-lattice microtubules, similar to tau9.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [9] Tan, R. et al. Microtubules gate tau condensation to spatially regulate microtubule functions. Nat. Cell Biol. 21, 1078–1085 (2019). source
The passage discussing Fig. 1i–j (page unavailable) reports diffuse tau binding on both taxol-stabilized and GMP-CPP microtubules, with condensates forming only on the former. This supports the broad comparison to tau, but the cited paper does not state that tau intensity outside condensates was identical to its intensity on GMP-CPP microtubules. The MAP2c measurement is the citing authors’ own result, not a result attributed to this source. (LLM, conf=0.78)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataMAP2c envelopes dissolved when exposed to 1,6-hexanediol, but the diffusive fraction of MAP2c molecules remained unchanged.
“Similar to tau9, MAP2c envelopes dissolved when exposed to 1,6-HD, but the diffusive fraction of MAP2c molecules remained unchanged”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [9] Tan, R. et al. Microtubules gate tau condensation to spatially regulate microtubule functions. Nat. Cell Biol. 21, 1078–1085 (2019). source
Classified as probably not a substantial claim.
Premisecitation1,6-Hexanediol disrupts phase separated systems in a variety of biological contexts.
“Tau envelopes are sensitive to the aliphatic alcohol 1,6-hexanediol (1,6-HD), a compound that disrupts phase separated systems in a variety of biological contexts9”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [9] Tan, R. et al. Microtubules gate tau condensation to spatially regulate microtubule functions. Nat. Cell Biol. 21, 1078–1085 (2019). source
The paper’s Abstract (page not available in our copy) reports that 1,6-hexanediol rapidly dissolved microtubule-bound tau condensates and notes that it has been shown to dissolve tau droplets formed by liquid–liquid phase separation. This supports the effect on tau systems, but the paper does not establish that it disrupts phase-separated systems across a variety of biological contexts. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationThe modest effect of MAP4 on the DDH landing rate may be consistent with prior results suggesting MAP4 could inhibit dynein-based movements.
“The modest effect of MAP4 on the DDH landing rate may be consistent with prior results18,19, which suggested MAP4 could inhibit dynein-based movements.”
Quote in the paperNot a substantial claim1 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe landing rate of dynein-dynactin complexes is strongly determined by the p150glued subunit of the dynactin complex.
“The landing rate of dynein-dynactin complexes is strongly determined by the p150glued subunit of the dynactin complex36”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [36] McKenney, R. J., Huynh, W., Vale, R. D. & Sirajuddin, M. Tyrosination of α-tubulin controls the initiation of processive dynein–dynactin motility. EMBO J. 35, 1175–1185 (2016). source
May combine two claims.
InterpretationcitationMAP4 adopts a conformation completely distinct from that of tau on microtubules, which may at least partially explain why MAP4 is unable to form envelopes.
“MAP4 adopts a conformation completely distinct from that of tau41,44 on microtubules, which may at least partially explain why, unlike tau, MAP4 is unable to form envelopes.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [41] Kellogg, E. H. et al. Near-atomic model of microtubule–tau interactions. Science 360, 1242–1246 (2018). source
- cites [44] Shigematsu, H. et al. Structural insight into microtubule stabilization and kinesin inhibition by Tau family MAPs. J. Cell Biol. 217, 4155–4163 (2018). source
The Results section (“Structural detail of MAP4–kinesin-1–microtubule binding”; page unavailable) suggests that 5R-MAP4 cannot adopt a Tau-like elongated structure in the presence of kinesin-1. It does not establish that MAP4’s conformation is completely distinct from Tau’s under all conditions, or address whether MAP4 can form envelopes. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn non-mammalian species, microtubule lattice compaction does not appear to be directly coupled to GTP hydrolysis.
“in non-mammalian species, microtubule lattice compaction does not appear to be directly coupled to GTP hydrolysis47,48.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [47] Howes, S. C. et al. Structural differences between yeast and mammalian microtubules revealed by cryo-EM. J. Cell Biol. 216, 2669–2677 (2017). source
The Conclusions report that dynamic yeast microtubules did not show the compaction seen in mammalian microtubules, but say this might reflect either less GTP hydrolysis or a different conformational response. The paper therefore does not establish that compaction is uncoupled from hydrolysis, and its yeast findings do not cover non-mammalian species generally. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [48] Chaaban, S. et al. The structure and dynamics of C. elegans tubulin reveals the mechanistic basis of microtubule growth. Dev. Cell 47, 191–204 (2018). source
The available copy yields only a corrupted table of contents, with no readable passage addressing whether microtubule lattice compaction is coupled to GTP hydrolysis. Searches for “lattice compaction GTP hydrolysis,” “compaction,” and an uncoupled-lattice paraphrase found no decisive text. (LLM, conf=0.72)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationRecent evidence suggests that the microtubule lattice is not conformationally homogenous, but releases and incorporates new GTP-tubulin subunits in response to mechanical damage and repair.
“recent evidence suggests that the microtubule lattice is not conformationally homogenous, but rather releases and incorporates new GTP-tubulin subunits in response to mechanical damage and repair49.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [49] Triclin, S. et al. Self-repair protects microtubules from destruction by molecular motors. Nat. Mater. 20, 883–891 (2021). source
May combine two claims.
PremisecitationMammalian tubulin within the GDP lattice primarily adopts a compacted state, whereas newly incorporated GTP tubulin adopts an expanded state.
“Mammalian tubulin within the GDP lattice primarily adopts compacted state, whereas the newly incorporated GTP tubulin adopts an expanded state1.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [1] Alushin, G. M. et al. High-resolution microtubule structures reveal the structural transitions in αβ-tubulin upon GTP hydrolysis. Cell 157, 1117–1129 (2014). source
The Results section (“High-resolution cryo-EM structures of dynamic and stabilized microtubules”; page unavailable) reports a shorter dimer repeat in the GDP lattice than in the expanded GMPCPP lattice, with compaction at the interface between dimers. But the study uses GMPCPP as a GTP-like analog; the Discussion (“Future Prospects”; page unavailable) cautions against treating its structure as the definitive GTP state. It therefore does not establish that newly incorporated GTP tubulin itself adopts that expanded state. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
InterpretationcitationAt high levels of tau, when the lattice is fully decorated, bending of the lattice leads to local decrease in tau densities, which could be explained by disruption of the tau envelope on stretched lattice on the outer side of the bend.
“By contrast, at high levels of tau, when the lattice is fully decorated by tau, bending of the lattice leads to local decrease in tau densities28, which could be explained by the disruption of the tau envelope on stretched lattice on the outer side of the bend.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [28] Siahaan, V. et al. Kinetically distinct phases of tau on microtubules regulate kinesin motors and severing enzymes. Nat. Cell Biol. 21, 1086–1092 (2019). source
The Additional information figure caption (p. unavailable) reports significantly lower tau density on highly curved microtubule regions than in islands on straight regions. The paper also reports saturation at high tau concentrations, but the cited passages do not establish that bending itself causes the density decrease under those conditions. The proposed disruption of a tau envelope appears after the citation as the citing authors’ explanation, not a finding attributed to this source. (LLM, conf=0.80)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationMAP4 did not block the binding of a kinesin-1 motor domain to microtubules in prior experiments, while the present study shows it negatively affects KIF1A motility.
“In prior experiments, MAP4 did not block the binding of a kinesin-1 motor domain to microtubules44, while we show that it negatively affects KIF1A motility.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [44] Shigematsu, H. et al. Structural insight into microtubule stabilization and kinesin inhibition by Tau family MAPs. J. Cell Biol. 217, 4155–4163 (2018). source
Classified as probably not a substantial claim. May combine two claims.
InterpretationcitationKinesin binding expands the microtubule lattice, suggesting that exclusive binding may arise from competition for an expanded versus compacted lattice.
“Apart from steric clashes between tau and kinesin9,41, kinesin binding expands the microtubule lattice4,6 suggesting that exclusive binding may arise from competition for an expanded versus compacted lattice.”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [4] Peet, D. R., Burroughs, N. J. & Cross, R. A. Kinesin expands and stabilizes the GDP-microtubule lattice. Nat. Nanotechnol. 13, 386–391 (2018). source
- cites [6] Shima, T. et al. Kinesin-binding–triggered conformation switching of microtubules contributes to polarized transport. J. Cell Biol. 217, 4164–4183 (2018). source
- cites [9] Tan, R. et al. Microtubules gate tau condensation to spatially regulate microtubule functions. Nat. Cell Biol. 21, 1078–1085 (2019). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationKIF1A is sensitive to the nucleotide state of the microtubule lattice.
“KIF1A, a neuronal cargo transporter critical for human health37–40 and sensitive to the nucleotide state of the microtubule lattice11.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [11] Guedes-Dias, P. et al. Kinesin-3 responds to local microtubule dynamics to target synaptic cargo delivery to the presynapse. Curr. Biol. 29, 268–282 (2019). source
May combine two claims.
Findingown dataTMR-MAP2c molecules transitioned to static binding within GFP-MAP2c envelopes, with dwell times increasing ~3-fold.
“However, TMR-MAP2c molecules transitioned to static binding within the GFP-MAP2c envelopes (Supplementary Fig. 3a), their dwell times increasing ~3-fold”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMAP2c colocalized with tau envelopes, where it was strongly enriched, showing that tau and MAP2c can form miscible MAP envelopes.
“Strikingly, MAP2c colocalized with the tau envelopes, where it was strongly enriched (Fig. 3g) showing that tau and MAP2c can form miscible MAP envelopes.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAt 20 nM tau, lattice regions not covered by tau envelopes showed no compaction, while regions covered by a tau envelope showed a compaction of 3.2 ± 1.0%.
“we found no compaction of the lattice in the regions of the microtubule not covered by tau envelopes, while the lattice regions covered by a tau envelope showed a compaction of 3.2 ± 1.0%”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMAP4 showed homogenous FRAP behavior with a recovery time and mobile fraction comparable to envelope-associated MAP2c.
“By contrast, MAP4 showed homogenous behavior with a recovery time and mobile fraction comparable to envelope-associated MAP2c”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMAP2c behaves similarly to tau, forming envelopes on taxol-lattice but not on GMPCPP-lattice microtubules.
“MAP2c behaved similarly to tau, forming envelopes on taxol-lattice but not on GMPCPP-lattice microtubules.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAfter adding 60 nM tau to a straight non-stretched microtubule held between optical traps, tau envelope formation was observed and force increased due to a decrease in bead distance, indicating microtubule lattice compaction.
“After adding 60 nM tau to the chamber we observed tau envelope formation (Fig. 2d) and, simultaneously, detected an increase in force due to a decrease in the distance between the two beads, indicating a compaction of the microtubule lattice”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe presence of MAP2c decreased SiR-tubulin binding by over 3-fold, while MAP4 had no effect.
“Similar to tau (Fig. 1i), the presence of MAP2c decreased SiR-tubulin binding by over 3-fold, while MAP4 had no effect”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMicrotubule compaction was observed within MAP2c envelopes, but not outside, and no compaction was observed upon addition of MAP4.
“Similar to tau, we observed compaction within MAP2c envelopes, but not outside (Fig. 3e). In contrast, we observed no microtubule compaction upon the addition of MAP4.”
Quote in the paperSubstantial claimMay combine two claims. The quote only partly states this claim.
Findingown dataOn taxol-lattice microtubules at 600 nM tau, kinesin-1 showed no movement, indicating full coverage by tau envelopes.
“After the addition of 60 nM kinesin-1, we observed no movement of kinesin-1 on the taxol-lattice microtubules, showing that these were fully covered by tau envelopes”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMAP4 does not form envelopes on either taxol-lattice or GMPCPP-lattice microtubules, but binds uniformly along the microtubule length.
“Conversely, we did not observe envelope formation on either lattice with MAP4, but rather uniform binding along the microtubule length”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn the presence of 10 μM taxol after flow, tau envelopes disassembled from the ends and from the location of the mechanically induced fissure, with tau density dropping to 3.6 ± 2.8%.
“After the hydrodynamic flow, in the presence of 10 μM taxol in solution, the envelopes disassembled from the ends. Additionally, the envelope started disassembling from the location where the fissure had been introduced by mechanical bending (Fig. 2a, Supplementary Movie 5) as evidenced by a drop in tau density to 3.6 ± 2.8% (Fig. 2a,b; mean ± s.d.).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTau envelope formation is a cooperative process, with a Hill coefficient of 1.9 ± 0.7.
“revealing that tau envelope formation is a cooperative process (Fig. 1b) with a Hill coefficient of 1.9 ± 0.7.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAt 600 nM tau, tau uniformly covers microtubules and envelopes cannot be distinguished by local changes in tau density.
“At this concentration, tau uniformly covers the microtubule and the envelopes cannot be distinguished by local changes in tau density.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataOn GMPCPP-lattice microtubules at 600 nM tau, kinesin-1 moved along entire lengths, indicating tau did not form envelopes even at saturating tau concentrations.
“By contrast, on the GMPCPP-lattice microtubules, kinesin-1 moved along their entire lengths, revealing that tau did not form envelopes, even at saturating tau concentrations.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSingle MAP4 molecules diffused on the microtubule lattice outside of tau/MAP2c envelopes but were unable to diffuse into the envelopes.
“while single MAP4 molecules diffused on the microtubule lattice outside of tau/MAP2c envelopes, they were unable to diffuse into the tau/MAP2c envelopes”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAfter addition of 400 nM tau to speckled taxol-lattice microtubules, envelopes formed rapidly and distances between individual speckles decreased, indicating lattice compaction concomitant with cooperative tau binding.
“After the addition of 400 nM tau to speckled taxol-lattice microtubules, envelopes formed rapidly and we observed a decrease in the distances between the individual speckles, indicating that the microtubule lattice was compacting concomitantly with the cooperative binding of tau”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn the absence of taxol, the fissure closed when the microtubule relaxed, with tau density recovering to 77.3 ± 10.8%.
“In the absence of taxol, the fissure closed when the microtubule relaxed, with the tau density recovering to 77.3 ± 10.8% (Fig. 2a,b, Supplementary Movie 6; mean ± s.d.).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAt higher concentrations, MAP2c and MAP4 strongly decreased the number of processive KIF1A motors without changing the velocity of motors that were able to bind.
“However, at higher concentrations these MAPs strongly decreased the number of processive motors without changing the velocity of motors that were able to bind”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAverage pixel intensities of KIF1A were negatively correlated with average intensities of MAP2c at both concentrations tested, whereas no negative correlation was observed between KIF1A and MAP4.
“The average pixel intensities of KIF1A were negatively correlated with the average intensities of MAP2c at both concentrations tested, whereas we did not observe a negative correlation between KIF1A and MAP4”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAt the highest concentrations of MAPs tested, MAP4, but not MAP2c, decreased the number of processive dynein motors on the microtubule.
“We found that at the highest concentrations of MAPs tested, MAP4, but not MAP2c, decreased the number of processive dynein motors on the microtubule”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataWithout substantial changes in initial tau density, fissures in the tau signal appeared and increased in size over time.
“Without substantial changes in the initial tau density on the microtubule, fissures in the tau signal appeared, which increased in size over time.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTau remained on microtubules when only DMSO was added, and the coefficient of variation remained largely unchanged.
“Tau remained on the microtubules when only DMSO was added to the medium, and the coefficient of variation remained largely unchanged”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataFor tau, cryo-EM showed a bimodal distribution of lattice spacing, suggesting the lattice was not covered entirely in tau envelopes under the conditions.
“For tau, we observed a bimodal distribution of lattice spacing, suggesting that the lattice was not covered entirely in tau envelopes under our conditions.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataTau envelope formation is tightly linked to microtubule mechanics, and physically extending microtubule lattices coated by tau envelopes induces envelope disassembly.
“Combined, these experiments establish that tau envelope formation is tightly linked to microtubule mechanics, and show that physically extending microtubule lattices coated by tau envelopes induces envelope disassembly”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningBecause MAP4 does not form envelopes, it is unable to provide spatially distinct regulation of motors and rather regulates them globally.
“Because MAP4 does not form envelopes, it is unable to provide spatially distinct regulation of motors and rather regulates them globally.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe sequence of the amplified MAP4 gene corresponds to the RefSeq NM_002375.5, as confirmed with Sanger sequencing.
“We confirmed that the sequence of the amplified gene corresponds to the RefSeq NM_002375.5 with Sanger sequencing.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataCompacted microtubule lattices induce cooperative binding of tau, and extending microtubule lattices induces disassembly of tau envelopes in vitro.
“Our results show that compacted microtubule lattices induce cooperative binding of tau, and that extending microtubule lattices induces disassembly of tau envelopes in vitro.”
Quote in the paperSubstantial claimMay combine two claims. The quote only partly states this claim.
Study design and conductown dataStaining for α-tubulin or co-transfecting with mScarlet-α-tubulin verified that microtubules were not disrupted by either treatment.
“Staining the cells for α-tubulin, or co-transfecting the cells with eGFP-tau and mScarlet-α-tubulin, verified that microtubules were not disrupted by either treatment”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataColocalization of tau and MAP2 into shared envelopes that exclude MAP4 suggests that different MAPs can form spatially distinct domains on the microtubule lattice, differentially regulating access to the microtubule surface.
“Colocalization of tau and MAP2 into shared envelopes that exclude MAP4 suggests that different MAPs can form spatially distinct domains on the microtubule lattice, differentially regulating access to microtubule surface.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataTau and MAP2, but not MAP4, are sensitive to the mechanical state of the microtubule lattice, and thus are suited to function as mechanosensitive MAPs.
“Our data suggests that tau and MAP2, but not MAP4, are sensitive to the mechanical state of the microtubule lattice, and thus are suited to function as mechanosensitive MAPs.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe trap stiffness was calibrated using force calibration (0.5.1) in Bluelake (v1.6.11, LUMICKS B.V.) under zero flow condition.
“The trap stiffness was calibrated using force calibration (0.5.1) in Bluelake (v1.6.11, LUMICKS B.V.) under zero flow condition.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenData points from two different protein preparations of mScarlet-tau envelopes were pooled.
“Data points from two different protein preparations of mScarlet–tau envelopes were pooled.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataLike tau, MAP2c forms envelopes that compact an extended microtubule lattice; MAP4 does not form cohesive envelopes in any condition tested and is unable to affect the structure of the lattice.
“Combined, these data reveal that like tau, MAP2c forms envelopes, which compact an extended microtubule lattice. By contrast, MAP4 does not form cohesive envelopes in any condition tested, and is unable to affect the structure of the lattice”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataTau/MAP2c envelopes exclude MAP4 at their boundaries and restrict the dynamics of MAP4 within.
“demonstrating that tau/MAP2c envelopes exclude MAP4 at their boundaries and restrict the dynamics of MAP4 within.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe vast majority of tau in U-2 OS cells was cooperatively bound to microtubules, and artificial lattice extension by taxol reveals this cooperative binding through envelope dissolution.
“We thus conclude that the vast majority of tau in U-2 OS cells was cooperatively bound to microtubules, and that artificial lattice extension by taxol reveals this cooperative binding through envelope dissolution.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThere was no observable negative correlation between averaged intensities of MAPs and DDH, suggesting neither MAP strongly affects the spatial distribution of the motors along microtubules.
“We found no observable negative correlation (Fig. 5d), suggesting that neither MAP strongly affects the spatial distribution of the motors along microtubules.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataMAP2c and MAP4 exert different effects on retrograde and anterograde motors, with MAP envelopes differentially regulating dynein-based retrograde and kinesin-based anterograde transport.
“These results indicate that cooperative envelope formation facilitates spatial regulation of the KIF1A motor along the microtubule, and demonstrate that MAP2c and MAP4 exert different effects on retrograde and anterograde motors.”
- Also stated in: § Discussion · boosted
“We demonstrate that MAP envelopes differentially regulate the motility of two predominant microtubule motor systems: dynein-based retrograde, and kinesin-based anterograde transport.”
Quote in the paperSubstantial claim- Also stated in: § Discussion · boosted
May combine two claims.
Interpretationown dataBoth MAP2c and MAP4 strongly affect the landing rate of KIF1A motors.
“These observations indicate that both MAPs strongly affect the landing rate of the KIF1A motors.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningCooperative binding of tau and MAP2c to microtubules both requires and reciprocally induces a local compaction of the underlying microtubule lattice.
“Cooperative binding of tau and MAP2c to microtubules both requires and, reciprocally, induces a local compaction of the underlying microtubule lattice.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll experiments were quantified by pooling data from at least two chambers performed on multiple days.
“All experiments were quantified by pooling data from at least two chambers performed on multiple days.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe sequence of the resulting pcDNA4.0/TO_EGFP-tau plasmid was checked using Sanger sequencing.
“The sequence of the resulting pcDNA4.0/TO_EGFP-tau plasmid was checked using Sanger sequencing.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataTau and MAP2 envelopes spatially gate kinesin access to the microtubule, while allowing dynein to pass.
“Our data reveal that tau and MAP2 envelopes spatially gate kinesin access to the microtubule, while allowing dynein to pass.”
Quote in the paperSubstantial claim
The authors state this as an assumption.
The majority of tubulin incorporated into microtubules in vivo, and the predominant volume of the microtubule lattice in cells, is in the compacted GDP state.
“Since the majority of tubulin incorporated to microtubules in vivo is thought to be in the compacted GDP-state”
“It is presumed that the predominant volume of the microtubule lattice in cells is in the GDP compacted state”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Phosphorylation likely also regulates tau-induced lattice compaction, misregulation of which could have downstream effects on microtubule stability and interactions with other MAPs and motor proteins.
“Phosphorylation likely also regulates tau-induced lattice compaction (Siahaan et al., 2022), in which misregulation of this process could have downstream effects on microtubule stability, as well as interactions with other MAPs and motor proteins.”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Siahaan et al., 2022
The Results section, “Tau cooperativity by local microtubule lattice compaction” (page unavailable), reports that lattice regions covered by tau envelopes compacted. Our copy does not establish that phosphorylation regulates this tau-induced compaction; a search for phosphorylation found no passage addressing that link. The proposed downstream effects are the citing authors’ inference, not the part directly attributed to this source. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe proline-rich region and C-terminal pseudo-repeat domain of tau regulate its cooperative interactions with microtubules.
“the proline-rich region and C-terminal pseudo-repeat domain of tau regulate its cooperative interactions with microtubules”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Siahaan et al., 2022
The Discussion (page unavailable) says regions flanking tau’s microtubule-binding repeats are required for envelope formation and might mediate interactions between tau molecules. It does not identify the proline-rich region and C-terminal pseudo-repeat domain specifically, so the claim’s domain-level attribution is not established by our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measuredProteins serving as 'conformational code readers' can become 'code writers' at a high concentration, an important feature of microtubule lattice plasticity.
“An important feature of microtubule lattice plasticity, in contrast to biochemical modifications, is that proteins serving as 'conformational code readers' can become 'code writers' at a high concentration 73 .”
From Taxane-induced conformational changes in the microtubule lattice activate GEF-H1-dependent RhoA signalling (2026) · cites this paper as [73]
Discontinuous patterning of tau along microtubules, consistent with envelopes, was observed in live non-neuronal U-2 OS cells following taxol treatment or elevated pH, and by immunofluorescence in fixed hippocampal neurons.
“Discontinuous patterning of tau along microtubules, consistent with envelopes, was also observed in live, non-neuronal U-2 OS cells following taxol treatment (Siahaan et al., 2022) or with elevated pH (Siahaan et al., 2026), and by immunofluorescence staining in fixed hippocampal neurons (Tan et al., 2019).”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Siahaan et al., 2022
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Flow assay says tau was removed but describes adding tau
MinorThe Results state that tau was removed during the hydrodynamic-flow assay and replaced with buffer. The corresponding Methods instead say that tau was introduced into the chamber, leaving the solution condition during envelope disassembly inconsistent.
“During the hydrodynamic flow, we removed tau from solution and added either buffer alone or buffer containing 10 μM taxol to further induce lattice extension.”
“After incubation, tau was removed from the measurement chamber by introducing 20 μl of tau in AB2 either in presence or absence of taxol (0 or 10 μM taxol).”
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Tyrosination of α‐tubulin controls the initiation of processive dynein–dynactin motility
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Self-citationMicrotubules gate tau condensation to spatially regulate microtubule functions
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Self-citationPhase separation of TPX2 enhances and spatially coordinates microtubule nucleation
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Severing enzymes amplify microtubule arrays through lattice GTP-tubulin incorporation
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τ Is Widely Expressed in Rat Tissues
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Kinetically distinct phases of tau on microtubules regulate kinesin motors and severing enzymes
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Self-citationSeparating the effects of nucleotide and EB binding on microtubule structure
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A combinatorial MAP code dictates polarized microtubule transport
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Self-citationEB1 Recognizes the Nucleotide State of Tubulin in the Microtubule Lattice
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Kinesin-3 responds to local microtubule dynamics to target synaptic cargo delivery to the presynapse
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Doublecortin Recognizes the 13-Protofilament Microtubule Cooperatively and Tracks Microtubule Ends
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Cryo-electron tomography reveals that dynactin recruits a team of dyneins for processive motility
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Self-citationFast Kinetics of Taxol Binding to Microtubules
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Tau interaction with microtubules in vivo
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Estimating the Microtubule GTP Cap Size In Vivo
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Self-citationKinesin-binding-triggered conformation switching of microtubules contributes to polarized transport
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MAP4 and CLASP1 operate as a safety mechanism to maintain a stable spindle position in mitosis
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The proline-rich domain promotes Tau liquid–liquid phase separation in cells
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Tau directs intracellular trafficking by regulating the forces exerted by kinesin and dynein teams
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Kinesin expands and stabilizes the GDP-microtubule lattice
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Acetylated Microtubules Are Preferentially Bundled Leading to Enhanced Kinesin-1 Motility
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Self-repair protects microtubules from destruction by molecular motors
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Structural differences between yeast and mammalian microtubules revealed by cryo-EM
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Purification of Tubulin from Porcine Brain
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Overexpression of MAP4 inhibits organelle motility and trafficking in vivo
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Mitochondria-adaptor TRAK1 promotes kinesin-1 driven transport in crowded environments
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The Structure and Dynamics of C. elegans Tubulin Reveals the Mechanistic Basis of Microtubule Growth
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The role of Tau protein in resistance to paclitaxel
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An evolutionary roadmap to the microtubule-associated protein MAP Tau
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Katanin‐mediated microtubule severing can be regulated by multiple mechanisms
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Self-citationDoublecortin Is Excluded from Growing Microtubule Ends and Recognizes the GDP-Microtubule Lattice
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Structural insight into microtubule stabilization and kinesin inhibition by Tau family MAPs
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Regulation of microtubule-based transport by MAP4
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Long-range, through-lattice coupling improves predictions of microtubule catastrophe
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Tau Avoids the GTP Cap at Growing Microtubule Plus-Ends
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Distinct neuronal localization of microtubule-associated protein 4 in the mammalian brain
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Intrinsically Disordered Domain of Kinesin-3 Kif14 Enables Unique Functional Diversity
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Self-citationMAP4 as a New Candidate in Cardiovascular Disease
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Microtubules Gate Tau Condensation to Spatially Regulate Microtubule FunctionsPreprint
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Self-citationTau Protein in Lung Smooth Muscle Cells
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Motor guidance by long-range communication through the microtubule highway
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Motor guidance by long-range communication through the microtubule highway
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Exploration and Suppression of Tau-Induced Cardiac and Skeletal Muscle Defects in a Drosophila Model
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Mechanism and regulation of kinesin motors.
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Tubulin polyglutamylation differentially regulates microtubule‐interacting proteins
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Self-citationPhase separation on microtubules: from droplet formation to cellular function?
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Self-citationA live-cell marker to visualize the dynamics of stable microtubules throughout the cell cycle
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Causes, costs and consequences of kinesin motors communicating through the microtubule lattice
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Liquid − liquid phase separation of tau: Driving forces, regulation, and biological implications
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Taxol acts differently on different tubulin isotypes
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Doublecortin restricts neuronal branching by regulating tubulin polyglutamylation
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Aging, NRF2, and TAU: A Perfect Match for Neurodegeneration?
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StableMARK-decorated microtubules in cells have expanded lattices
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Microtubule‐associated proteins and enzymes modifying tubulin
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Structural switching of tubulin in the microtubule lattice
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How do neurons age? A focused review on the aging of the microtubular cytoskeleton
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MAP9/MAPH-9 supports axonemal microtubule doublets and modulates motor movement
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Competition for microtubule lattice spacing between a microtubule expander and compactor
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Beyond uniformity: Exploring the heterogeneous and dynamic nature of the microtubule lattice
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Partial mimicry of the microtubule binding of tau by its membrane binding
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Tannic acid as a biphasic modulator of tau protein liquid–liquid phase separation
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Microtubule-associated protein, MAP1B, encodes functionally distinct polypeptides
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Abl2 repairs microtubules and phase separates with tubulin to promote microtubule nucleation
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Tau oligomerization on microtubules in health and disease
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Self-citationAntagonistic roles of tau and MAP6 in regulating neuronal development
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KIF2A stabilizes intercellular bridge microtubules to maintain mouse embryonic stem cell cytokinesis
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The GTP-tubulin cap is not the determinant of microtubule end stability in cells
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Liu, H., Yamaguchi, H., Kikkawa, M., & Shima, T. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.04.30.591984 · Cited by 7 · see citing works
Lucena-Agell, D., Fernández, Ó., París-Ogáyar, R., Estévez-Gallego, J., Ondrúšková, D., Álvarez-Bernad, B., Bonato, F., Larraga, J., de Elguea, D. O., Cano, G. J., et al. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2532791123 · Cited by 6 · see citing works
Self-citationMicrotubules in the axon are GDP bound but adopt a stable GTP-like expanded state
Zehr, E. A., Sun, S., Sarbanes, S. L., & Roll-Mecak, A. (2026) · Nature Structural & Molecular Biology · doi:10.1038/s41594-026-01787-7 · Cited by 8 · see citing works
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Microtubules composed of α4A undergo curved growth mainly mediated by its core structure
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Ionic strength alters crosslinker‐driven self‐organization of microtubules
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Electrostatic Effects on Tau Nanocondensates
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Myosin II–independent contraction of actin filaments in membrane nanotubes
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Injury-induced tau pathology promotes aggressive behavior in Drosophila without neurodegeneration
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The Effect of Tau on Dynamics of Kinesin Motor
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Feeling a nanoworld with optical tweezers: Hands on training at IUPAB 2024
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Dynamic conformational ensembles of soluble Tau encode neuronal toxicity prior to aggregationPreprint
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Taxol exploits molecular switches within tubulin to stabilize microtubulesPreprint
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Molecular Grammar of Microtubule-Wetting CondensatesPreprint
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SSNA1 mechanically reinforces the damaged microtubule latticePreprint
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Caractérisation d'un nouveau mode de fixation de la protéine Tau aux microtubules
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Tau phosphorylation impedes functionality of protective tau envelopes
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- Authors
- Siahaan, V., Tan, R., Humhalova, T., Libusova, L., Lacey, S. E., Tan, T., Dacy, M., Ori-McKenney, K. M., McKenney, R. J., Braun, M., & Lansky, Z.
- Affiliations
- Czech Academy of Sciences (CZ)
- University of California, Davis (US)
- MRC Laboratory of Molecular Biology (GB)
- Corresponding author
- Ori-McKenney, Kassandra M.
- McKenney, Richard J.
- Braun, Marcus
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2022-08-22
- Volume
- 18
- Issue
- 11
- Pages
- 1224-1235
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC9613621
- OpenAlex
- W4292641506
- Cited by
- 94
- References
- 93
- Citations by year
- 2026: 32 · 2025: 23 · 2024: 14 · 2023: 23 · 2022: 2
- FWCI
- 8.28
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Chemical Biology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Univerzita Karlova v Praze (CZ.02.2.69/0.0/0.0/19\_073/0016935, 02.2.69/0.0/0.0/19_073/0016935, CZ.02.1.01/0.0/0.0/16_013/0001775, 86652036)
- Grantová Agentura, Univerzita Karlova (CZ.02.1.01/0.0/0.0/16_013/0001775, CZ.02.2.69/0.0/0.0/19_073/0016935)
- Ministerstvo Školství, Mládeže a Tělovýchovy (CZ.02.1.01/ 0.0/0.0/16 013/0001775, LM2018129, CZ.02., CZ.02.2.69/0.0/0.0/19 073/0016935, CZ.02.1.01, LM2015043, CZ.02.1.01/0.0, 86652036)
- Grantová Agentura České Republiky (CZ.02.1.01/0.0, 86652036, CZ.02.1.01, CZ.02.2.69/0.0/0.0/19 073/0016935, GX19-27477X, CZ.02.1.01/0.0/0.0/16_013/0001775, LM2018129, LM2015043, GA20-04068S, /19_073/0016935)
- European Regional Development Fund (02.1.01/0.0/0.0, CZ.02.2.69/0.0/0.0/19_073/0016935, CZ.02, CZ.02.1.01, CZ.02.1.01/0.0, /16_013/0001775, LM2018129, CZ.02.1.01/0.0/0.0, CZ.02.1.01/0.0/0.0/16_013/0001775, 86652036)
- National Institute of General Medical Sciences (R35GM124889, R35GM133688)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- tau protein, microtubule-associated proteins, MAP2, MAP4, intrinsically disordered proteins, tubulin dimers, allosteric regulation, neurodegeneration
- MeSH terms
- Humans, Microtubule-Associated Proteins, Microtubules, Proteins, Tubulin, tau Proteins, Neurodegenerative Diseases
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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.
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