Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau

In the paper

“This is likely due of differences in ionic strength, because previous studies used phosphate buffer7, while we chose general actin assembly buffer.”

What the sources say

• Disputed

  The Methods section ('Tau interaction with microtubules or F-actin'; page unavailable) says the cited study measured Tau/F-actin binding in AP (actin-polymerization) buffer, not phosphate buffer. The Results section ('Tau simultaneously binds to microtubules and actin filaments'; page unavailable) reports the dissociation constant but does not attribute a difference from a previously reported value to ionic strength. (LLM, conf=0.85)

  Checked by a reasoning model — may be wrong.

  cites [7] Elie, A. et al. Tau co-organizes dynamic microtubule and actin networks. Sci. Rep. 5, 9964 (2015). sourceExperimental — accuracy not yet measured

In the paper

“According to the resonance assignment of Tau27, cross-peaks from residues such as S262, N265, and T319 were strongly attenuated.”

What the sources say

• Supported

  The citation in the printed sentence identifies the source of Tau’s resonance assignments; it does not attribute the F-actin attenuation experiment to that source. In Results, “Backbone Resonance Assignment of 441-Residue Tau” (page unavailable), the paper reports assigning more than 98% of non-proline backbone resonances and lists the exceptions, which do not include S262, N265, or T319. (LLM, conf=0.89)

  cites [27] Mukrasch, M. D. et al. Structural polymorphism of 441-residue tau at single residue resolution. PLoS Biol. 7, e34 (2009). source

In the paper

“The derived dissociation constant is lower than a previously reported value of 241 ± 43 nM7.”

What the sources say

• Supported

  The Results section ('Tau simultaneously binds to microtubules and actin filaments') reports a Tau/F-actin apparent dissociation constant of 241 ± 43 nM. This supports the cited benchmark; the lower derived value belongs to the citing study, not to this source. (LLM, conf=0.93)

  cites [7] Elie, A. et al. Tau co-organizes dynamic microtubule and actin networks. Sci. Rep. 5, 9964 (2015). source

In the paper

“Binding of Tau and MAP2 to filamentous actin results in actin cross-linking and filament bundling5, 6, 14, 22, 40–43.”

What the sources say

• ?Not checked — no full text of the sourcecites [5] Sattilaro, R. F. Interaction of microtubule-associated protein 2 with actin filaments. Biochemistry 25, 2003–2009 (1986). source
• ?Not checked — no full text of the sourcecites [6] Selden, S. C. & Pollard, T. D. Phosphorylation of microtubule-associated proteins regulates their interaction with actin filaments. J. Biol. Chem. 258, 7064–7071 (1983). source
• ?Could not verify

  The Introduction (p. 717) discusses possible tau-mediated cross-linking and bundling of microtubules, not actin filaments. Searches for filamentous actin, actin binding, and actin bundling found no passage in our copy addressing the claimed effects of tau and MAP2 on actin. (LLM, conf=0.76)

  cites [14] Butner, K. A. & Kirschner, M. W. Tau protein binds to microtubules through a flexible array of distributed weak sites. J. Cell. Biol. 115, 717–730 (1991). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [22] Fulga, T. A. et al. Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo. Nat. Cell. Biol. 9, 139–148 (2007). source
• ?Not checked — no full text of the sourcecites [40] Thomas, D. D., Seidel, J. C. & Gergely, J. Rotational dynamics of spin-labeled F-actin in the sub-millisecond time range. J. Mol. Biol. 132, 257–273 (1979). source
• ?Not checked — no full text of the sourcecites [41] Yoshimura, H. et al. Torsional motion of eosin-labeled F-actin as detected in the time-resolved anisotropy decay of the probe in the sub-millisecond time range. J. Mol. Biol. 179, 453–467 (1984). source
• ?Could not verify

  The Discussion describes caspase-cleaved tau assembling into tau filaments and mentions MAP2 only as a related protein. Searches for actin cross-linking, filament bundling, and binding to filamentous actin found no passage in our copy addressing the claimed Tau–MAP2 interaction with actin. (LLM, conf=0.76)

  cites [42] Gamblin, T. C. et al. Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer’s disease. Proc. Natl Acad. Sci. USA 100, 10032–10037 (2003). sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Introduction and Results discuss tau’s effects on microtubules and the formation of tau filaments, not binding to filamentous actin. Searches for actin, MAP2, cross-linking, and bundling found no passage in our copy addressing the claimed effect. (LLM, conf=0.75)

  cites [43] Zhang, Z. et al. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease. Nat. Med. 20, 1254–1262 (2014). sourceExperimental — accuracy not yet measured

In the paper

“At the same time, binding to F-actin can be retained, but the cross-linking activity disrupted.”

What the sources say

• ?Not checked — no full text of the sourcecites [5] Sattilaro, R. F. Interaction of microtubule-associated protein 2 with actin filaments. Biochemistry 25, 2003–2009 (1986). source
• Supported

  The Results report that the synthetic tau peptide binds F-actin but cannot bundle actin filaments (Fig. 4). The paper contrasts this with whole tau, which does bundle filaments, supporting the distinction between retained binding and disrupted cross-linking activity in the peptide. (LLM, conf=0.91)

  cites [17] Correas, I., Padilla, R. & Avila, J. The tubulin-binding sequence of brain microtubule-associated proteins, tau and MAP-2, is also involved in actin binding. Biochem. J. 269, 61–64 (1990). source

In the paper

“cellular studies showed that phosphorylation of the KXGS motifs cause MAP2 and Tau to localize to the actin cytoskeleton9.”

What the sources say

• Partly supported

  The Discussion reports a cellular study in which phosphorylation of MAP2’s KXGS motifs led to its translocation to the actin network. For Tau, however, the paper says it “hypothesize[s]” such translocation; the cellular observations described there show MARK2, not phosphorylated Tau, colocalizing with actin. The claim overstates the Tau finding as demonstrated. (LLM, conf=0.90)

  cites [9] Biernat, J. et al. Protein kinase MARK/PAR-1 is required for neurite outgrowth and establishment of neuronal polarity. Mol. Biol. Cell. 13, 4013–4028 (2002). sourceExperimental — accuracy not yet measured

In the paper

“in agreement with experimentally observed cross-linking of microtubules and actin filaments by Tau7.”

What the sources say

• Supported

  The Results section (‘Tau simultaneously binds to microtubules and actin filaments’) reports that hybrid bundles of co-aligned microtubules and actin filaments appeared in the presence of Tau. The Discussion identifies Tau as a molecular linker between the two in an in vitro system, supporting the cited description of experimentally observed cross-linking. (LLM, conf=0.94)

  cites [7] Elie, A. et al. Tau co-organizes dynamic microtubule and actin networks. Sci. Rep. 5, 9964 (2015). source

In the paper

“Interaction with the proline-rich region is primarily of electrostatic nature58.”

What the sources say

• Partly supported

  The Discussion hypothesizes that electrostatic force underlies the interaction between tau’s proline-rich domain and actin, and reports that increasing ionic strength weakens the interaction. The claim presents this proposed mechanism as established and primarily electrostatic, which the paper does not demonstrate. (LLM, conf=0.85)

  cites [58] He, H. J. et al. The proline-rich domain of tau plays a role in interactions with actin. BMC Cell Biol. 10, 81 (2009). sourceExperimental — accuracy not yet measured

In the paper

“Tau has also been found on dynamic microtubules in the actin rich growth cone areas of developing neurons71.”

What the sources say

• Supported

  The Results report tau on microtubules in growth cones. The Discussion identifies microtubules in the distal axon and growth cone as among the most dynamic, supporting the citing sentence’s central claim. (LLM, conf=0.89)

  cites [71] Black, M. M., Slaughter, T., Moshiach, S., Obrocka, M. & Fischer, I. Tau is enriched on dynamic microtubules in the distal region of growing axons. J. Neurosci. 16, 3601–3619 (1996). source

In the paper

“Consistent with these findings in cells, Tau binds in vitro simultaneously to microtubules and actin filaments7.”

What the sources say

• Supported

  In the Results section, under “Tau simultaneously binds to microtubules and actin filaments” (page not provided), an in vitro co-sedimentation assay found that F-actin sedimented with microtubules only when tau was present. The authors interpret this as evidence that tau simultaneously interacts with both filament networks. (LLM, conf=0.94)

  cites [7] Elie, A. et al. Tau co-organizes dynamic microtubule and actin networks. Sci. Rep. 5, 9964 (2015). source

In the paper

“We previously showed that the Tau residues 168–185, 224–237, 245–253, 269–284, 300–313, and 375–398 bind to microtubules at the interface between tubulin heterodimers (Fig. 5b)72.”

What the sources say

• Partly supported

  The Significance passage (p. 2) identifies residues 224–237 and 245–253 as microtubule-binding motifs, and the paper states that Tau binds at the interface between tubulin heterodimers (p. 1). But it gives the other measured motifs as 275–284 and 300–317, not 269–284 and 300–313. The available passages do not identify 168–185 or 375–398 as binding motifs at that precise interface. (LLM, conf=0.86)

  cites [72] Kadavath, H. et al. Tau stabilizes microtubules by binding at the interface between tubulin heterodimers. Proc. Natl Acad. Sci. USA 112, 7501–7506 (2015). sourceExperimental — accuracy not yet measured

In the paper

“This hydrophobic pocket is solvent-accessible on the surface of actin filaments59–61.”

What the sources say

• ?Not checked — no full text of the sourcecites [59] Dominguez, R. Actin-binding proteins--a unifying hypothesis. Trends Biochem. Sci. 29, 572–578 (2004). source
• Partly supported

  The Actin Monomer section identifies a predominantly hydrophobic cleft between subdomains 1 and 3. The G- to F- Transition section says an actin-binding domain can bind in that cleft on F-actin, but the paper does not explicitly establish that the pocket is solvent-accessible on the filament surface; it also describes a neighboring subunit’s D-loop occupying part of the cleft. (LLM, conf=0.79)

  cites [60] Dominguez, R. & Holmes, K. C. Actin structure and function. Annu Rev. Biophys. 40, 169–186 (2011). sourceExperimental — accuracy not yet measured
• Not checked yetcites [61] Schoenenberger, C. A., Mannherz, H. G. & Jockusch, B. M. Actin: from structural plasticity to functional diversity. Eur J Cell Biol 90, (797–804 (2011).

In the paper

“The analysis reveals that the proline-rich regions P1–P2 and the four pseudo-repeats contribute to the Tau/F-actin interaction.”

In the paper

“Comparison with a reference spectrum of Tau alone showed that addition of F-actin into the Tau pool decreased the signal intensity of several Tau residues (Fig. 1e and Supplementary Fig. 2).”

In the paper

“In addition, ~8% of Tau molecules were bound to single filaments, while ~29% of Tau was found together with actin bundles.”

In the paper

“A fit to the experimental data using a single-binding site model resulted in a dissociation constant of 60 ± 10 nM.”

In the paper

“Consistent with these data, we showed that phosphorylation of Tau by MARK2 reduces the affinity of Tau for F-actin (Fig. 4d) and prevents F-actin bundling (Fig. 4e).”

In the paper

“The directionality of the Tau(259–267)-helix is similar to that of the actin-interacting helix of toxofilin (Supplementary Fig. 9), an actin-binding protein that is secreted into host cells during invasion60.”

In the paper

“The comparison showed that the helical region of Tau(254–290) is positioned in the binding pocket in a similar way as the recognition helix of cofilin (blue).”

In the paper

“Consistent with a reduced affinity, MARK2-phosphorylated Tau failed in bundling actin filaments (Fig. 4e).”

In the paper

“In agreement with a decrease in affinity of Tau(254–290)-L266E for binding to F-actin (Supplementary Fig. 1), the mutant peptide was less efficient in promoting F-actin bundling (Supplementary Fig. 10f).”

In the paper

“Within the highest scoring cluster (Supplementary Fig. 8), the N-terminal helical region of Tau(254–290) was bound to the hydrophobic pocket of F-actin (Fig. 3e).”

In the paper

“Consistent with this hypothesis, we showed that a single Tau helix is sufficient for binding to F-actin, but at least two helices, which are separated by a flexible linker, are required for cross-linking activity (Supplementary Figs. 5, 13 and 14).”

In the paper

“Indeed, K18 bound with a Kd of 110 ± 1 nM to F-actin (Supplementary Fig. 1).”

In the paper

“We identified Tau residues that are important for complex formation and provided high-resolution information about the structural changes that occur in Tau upon binding to filamentous actin.”

In the paper

“The PRE profile contained seven peaks corresponding to Tau residues L243-A246, K259-K267, V275-L284, S289-S293, S305-V313, S320-H330, and K375-F378 (Fig. 2e, Supplementary Fig. 4c).”

In the paper

“In agreement with a structural model of Tau repeat sequences in complex with actin filaments, phosphorylation at serine 262 attenuates binding of Tau to filamentous actin.”

In the paper

“In agreement with the NMR data, addition of cofilin decreased the amount of Tau that co-sedimented with F-actin (Fig. 2c).”

In the paper

“We identified Tau residues that are important for complex formation and provided high-resolution information about the structural changes that occur in Tau upon binding to filamentous actin.”

In the paper

“Because Tau contains seven actin-binding segments (Fig. 2e), up to seven actin filaments could be linked together by a single Tau molecule.”

In the paper

“When compared to the wild-type peptide, Tau(254–290)-L266E showed a decreased STD signal (Supplementary Figure 10c–e), indicating that the mutation attenuated F-actin binding.”

In the paper

“Two helical regions, which are separated from each other by flexible residues, are formed in Tau(254–290) upon binding to F-actin (Fig. 3c, d).”

In the paper

“In agreement with the ability of Tau(292–319) to bind to F-actin, the peptide promotes bundling of actin filaments (Supplementary Fig. 5c).”

In the paper

“The side chain of S262 points towards actin’s hydrophobic binding pocket (Fig. 3e), providing a structural explanation for the lower affinity of S262-phosphorylated Tau(254–284).”

In the paper

“In this model, L266 of Tau(254–290) is 4 Å away from I345 of F-actin, while the HE atom of the cofilin residue M115 is 3.1 Å separated from the HG2 atom of actin’s I341.”

In the paper

“In contrast, medium-range NOE cross-peaks, which are specific for secondary structure, were observed for residues ~260 to ~268 and residues ~277 to ~283.”

In the paper

“The analysis showed that the N- and C terminus of Tau(254–290) remain unstructured in complex with F-actin.”

In the paper

“In addition, attachment of a phosphate group to S262 in the peptide Tau(254–284) decreased the affinity of the peptide for F-actin (Supplementary Fig. 1) and lowered the amount of Tau(254–284)-promoted actin bundles (Fig. 4f).”

In the paper

“In addition, attachment of a phosphate group to S262 in the peptide Tau(254–284) decreased the affinity of the peptide for F-actin (Supplementary Fig. 1) and lowered the amount of Tau(254–284)-promoted actin bundles (Fig. 4f).”

In the paper

“In addition, specific phosphorylation at S262 decreased the F-actin affinity of Tau(254–284) (Supplementary Fig. 1) and decreased the peptides bundling activity (Fig. 4f).”

In the paper

“In addition, K18 was capable of bundling F-actin (Supplementary Fig. 5b).”

In the paper

“Consistent with these data, we showed that phosphorylation of Tau by MARK2 reduces the affinity of Tau for F-actin (Fig. 4d) and prevents F-actin bundling (Fig. 4e).”

In the paper

“The downfield chemical shift of phosphorylated residues (Fig. 4a) is in agreement with previous reports and confirms phosphorylation at S262, S293, S305, S324, S356, and S41654.”

What the sources say

• ?Not checked — no full text of the sourcecites [54] Schwalbe, M. et al. Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2. Biochemistry 52, 9068–9079 (2013). source

In the paper

“Consistent with this hypothesis, we showed that a single Tau helix is sufficient for binding to F-actin, but at least two helices, which are separated by a flexible linker, are required for cross-linking activity (Supplementary Figs. 5, 13 and 14).”

In the paper

“In contrast to Tau(254–290), however, Tau(254–268) was not able to bundle F-actin (Supplementary Fig. 5d).”

In the paper

“In addition, specific phosphorylation at S262 decreased the F-actin affinity of Tau(254–284) (Supplementary Fig. 1) and decreased the peptides bundling activity (Fig. 4f).”

In the paper

“To gain insight into the structure, which these segments adopt in complex with F-actin, we used the peptide Tau(254–290), which bundles filaments (Fig. 3a).”

In the paper

“In addition, I260 of Tau(254–290) was found in a similar location as I124 from cofilin.”

In the paper

“Sequential resonance assignment of the peptide (Supplementary Table 3), followed by NOE analysis (Supplementary Fig. 13) and structure calculations (Supplementary Fig. 14) showed that the short peptide folds into an α-helix (residues 259–265) in complex with F-actin that is similar to the one found in Tau(254–290) (Supplementary Fig. 14b).”

In the paper

“The KXGS motif, which contains S262, is located in one of the F-actin interacting helices of Tau (Fig. 3c).”

In the paper

“The data demonstrate that Tau bundles actin filaments.”

In the paper

“Very little chemical shift changes were observed, indicating that the binding process is intermediate to slow on the NMR time scale.”

In the paper

“In agreement with the disease relevance of the Tau/actin interaction, actin-rich paracrystalline inclusions, so-called Hirano bodies, are found in brain histopathological samples of AD and related tauopathies24, 25.”

What the sources say

• ?Not checked — no full text of the sourcecites [24] Hirano, A. Hirano bodies and related neuronal inclusions. Neuropathol. Appl. Neurobiol. 20, 3–11 (1994). source
• ?Not checked — no full text of the sourcecites [25] Makioka, K., Yamazaki, T., Takatama, M., Ikeda, M. & Okamoto, K. Immunolocalization of Smurf1 in Hirano bodies. J. Neurol. Sci. 336, 24–28 (2014). source

In the paper

“Occurrence of Tau deposits correlates with the loss of cognitive functions in AD, suggesting a connection between Tau and synaptic transmission20.”

What the sources say

• ?Not checked — no full text of the sourcecites [20] Giannakopoulos, P. et al. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology 60, 1495–1500 (2003). source

In the paper

“In addition, short fragments of the microtubule-binding domain of Tau promote actin bundling16.”

What the sources say

• ?Not checked — no full text of the sourcecites [16] Moraga, D. M., Nunez, P., Garrido, J. & Maccioni, R. B. A tau fragment containing a repetitive sequence induces bundling of actin filaments. J. Neurochem. 61, 979–986 (1993). source

In the paper

“In addition, phosphorylation by endogenous protein kinases inhibits the ability of Tau and MAP2 to cross-link and bundle actin filaments5, 6.”

What the sources say

• ?Not checked — no full text of the sourcecites [5] Sattilaro, R. F. Interaction of microtubule-associated protein 2 with actin filaments. Biochemistry 25, 2003–2009 (1986). source
• ?Not checked — no full text of the sourcecites [6] Selden, S. C. & Pollard, T. D. Phosphorylation of microtubule-associated proteins regulates their interaction with actin filaments. J. Biol. Chem. 258, 7064–7071 (1983). source

In the paper

“The above data suggest that Tau does not bind as a single rigid entity to F-actin.”

In the paper

“These findings suggest that multiple domains of Tau might be required for actin cross-linking.”

In the paper

“The docking model (Fig. 3e) suggests an important role of the Tau residue L266 for binding to F-actin.”

In the paper

“The analysis suggests that the experimental NOE data witness the formation of helical structure in these regions upon binding to F-actin, but the number of detected restraints is not sufficient to define a unique conformation.”

In the paper

“Analysis of NOE signal intensities as a function of mixing time suggested that spin diffusion did not significantly contribute to the observed NOE intensities (Supplementary Fig. 6a).”

In the paper

“Because of the simultaneous observation of line broadening upon addition of diamagnetic F-actin (Fig. 1f; Supplementary Fig. 2), the exchange process is intermediate on the NMR chemical shift time scale.”

In the paper

“Thus, two Tau interaction sites have to be present, in order to bundle F-actin filaments.”

In the paper

“Instead, short hydrophobic Tau segments, which are separated from each other by flexible residues, bind dynamically to actin’s hydrophobic pocket (Fig. 2).”

In the paper

“Because this region showed less sequence-specific variation, we suggest that the broadening effect is the result of unspecific binding of the N-terminal half of Tau to the surface of F-actin.”

In the paper

“After addition of cofilin, Tau’s NMR resonance intensities and positions were similar to those in the absence of F-actin (Fig. 2b), indicating that (i) Tau is no longer bound to F-actin and (ii) cofilin does not bind to Tau.”

In the paper

“Taken together the data show that Tau utilizes a structural mechanism for binding to F-actin that is used by actin-binding proteins.”

In the paper

“suggest that Tau binds to the solvent-exposed hydrophobic pocket that is located between subdomains 1 and 3 of actin.”

• Also stated in: § Abstract · plain

  “We show that Tau uses several short helical segments to bind in a dynamic, multivalent process to the hydrophobic pocket between subdomains 1 and 3 of actin.”

In the paper

“Steric constraints are minimized by the presence of flexible linkers between the seven actin-binding segments.”

In the paper

“On this basis, we developed a model, in which two helical regions in Tau are bound to two different actin filaments (Fig. 5a).”

In the paper

“Phosphorylation of serine residues at KXGS motifs in the repeat domain of Tau, such as S262, strongly reduce the affinity of Tau for microtubules75.”

What the sources say

• ?Not checked — no full text of the sourcecites [75] Biernat, J., Gustke, N., Drewes, G., Mandelkow, E. M. & Mandelkow, E. Phosphorylation of Ser262 strongly reduces binding of tau to microtubules: distinction between PHF-like immunoreactivity and microtubule binding. Neuron 11, 153–163 (1993). source

In the paper

“The analysis suggests that the experimental NOE data witness the formation of helical structure in these regions upon binding to F-actin, but the number of detected restraints is not sufficient to define a unique conformation.”

In the paper

“The transfer-NOE data thus point to the formation of helical structure in Tau(292–319) upon binding to F-actin, but the number of detected restraints was not sufficient to define a unique conformation.”

In the paper

“After addition of cofilin, Tau’s NMR resonance intensities and positions were similar to those in the absence of F-actin (Fig. 2b), indicating that (i) Tau is no longer bound to F-actin and (ii) cofilin does not bind to Tau.”

In the paper

“The side chain of S262 points towards actin’s hydrophobic binding pocket (Fig. 3e), providing a structural explanation for the lower affinity of S262-phosphorylated Tau(254–284).”

In the paper

“The NMR experiments demonstrate that MARK2-phosphorylation of Tau attenuates its binding to F-actin.”

In the paper

“Thus, phosphorylation within one of the seven interaction motifs of Tau (e.g. S262 in the helical segment formed by residues ~260 to ~268; Figs. 2 and 3c) weakens the interaction of this motif with F-actin, in agreement with the structural studies (Fig. 3).”

In the paper

“The lower affinity when compared to full-length Tau is in agreement with the contribution of regions outside of the repeat domain to the F-actin interaction (Figs. 1f and 2b, e; Supplementary Fig. 2).”

In the paper

“The multivalent interaction of Tau with F-actin and microtubules results in cross-linking of the cellular cytoskeleton.”

In the paper

“In addition, the excess positive charge, which is present in the repeat domain of Tau, will decrease electrostatic repulsion between the negatively charged filament surfaces.”

In the paper

“Because Tau contains seven actin-binding segments (Fig. 2e), up to seven actin filaments could be linked together by a single Tau molecule.”

In the paper

“Consistent with the compatibility of these regions for helical conformation, Tau residues 253–260, 315–322, and 345–354 populate helical structure in the presence of detergent and upon binding to membranes65.”

What the sources say

• ?Not checked — no full text of the sourcecites [65] Barre, P. & Eliezer, D. Folding of the repeat domain of tau upon binding to lipid surfaces. J. Mol. Biol. 362, 312–326 (2006). source

In the paper

“We show that Tau uses several short helical segments to bind in a dynamic, multivalent process to the hydrophobic pocket between subdomains 1 and 3 of actin.”

In the paper

“Although a single Tau helix is sufficient to bind to filamentous actin, at least two, flexibly linked helices are required for actin bundling.”

In the paper

“The observation that cofilin, but no Tau, co-precipitates with actin filaments (Fig. 2c) also indicates that actin filaments were not disassembled by cofilin.”

In the paper

“Instead, the presence of a proline residue followed by three glycines in between the two helical regions suggests that the intervening residues remain flexible.”

In the paper

“Although a single Tau helix is sufficient to bind to filamentous actin, at least two, flexibly linked helices are required for actin bundling.”

In the paper

“We further showed that the F-actin-interacting residues in the repeat domain of Tau, fold into short helices upon binding to filamentous actin (Fig. 3 and Supplementary Figs. 12 and 14).”

In the paper

“Both findings together suggest that localization of phosphorylated Tau to actin-containing structures might be mediated by additional actin-binding proteins.”

In the paper

“In addition, Tau-induced neurotoxicity is associated with increased F-actin levels22, and Tau-induced remodeling of the actin cytoskeleton can cause plasma membrane blebbing57.”

What the sources say

• ?Not checked — no full text of the sourcecites [22] Fulga, T. A. et al. Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo. Nat. Cell. Biol. 9, 139–148 (2007). source

In the paper

“While our as well as previous biophysical studies demonstrated that phosphorylation at the KXGS motifs decreases the affinity of Tau for both microtubules and F-actin, cellular studies showed that phosphorylation of the KXGS motifs cause MAP2 and Tau to localize to the actin cytoskeleton9.”

What the sources say

• ?Not checked — no full text of the sourcecites [75] Biernat, J., Gustke, N., Drewes, G., Mandelkow, E. M. & Mandelkow, E. Phosphorylation of Ser262 strongly reduces binding of tau to microtubules: distinction between PHF-like immunoreactivity and microtubule binding. Neuron 11, 153–163 (1993). source
• ?Not checked — no full text of the sourcecites [5] Sattilaro, R. F. Interaction of microtubule-associated protein 2 with actin filaments. Biochemistry 25, 2003–2009 (1986). source
• ?Not checked — no full text of the sourcecites [6] Selden, S. C. & Pollard, T. D. Phosphorylation of microtubule-associated proteins regulates their interaction with actin filaments. J. Biol. Chem. 258, 7064–7071 (1983). source

In the paper

“Observation of PRE broadening at the chemical shift of unbound Tau demonstrates that the Tau molecule exchanges between the F-actin-bound and free state.”