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Cited by 154Alzheimer's disease research and treatmentsMicrotubule and mitosis dynamicsCellular Mechanics and Interactions

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

Open access
Cabrales Fontela, Yunior, Kadavath, Harindranath, Biernat, Jacek, Riedel, Dietmar, Mandelkow, Eckhard, Zweckstetter, Markus·2017·Nature Communications
DOI 10.1038/s41467-017-02230-8PMC PMC5719408
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Abstract

Microtubule-associated proteins regulate microtubule dynamics, bundle actin filaments, and cross-link actin filaments with microtubules. In addition, aberrant interaction of the microtubule-associated protein Tau with filamentous actin is connected to synaptic impairment in Alzheimer’s disease. Here we provide insight into the nature of interaction between Tau and actin filaments. 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. Although a single Tau helix is sufficient to bind to filamentous actin, at least two, flexibly linked helices are required for actin bundling. 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. Taken together the data demonstrate that bundling of filamentous actin and cross-linking of the cellular cytoskeleton depend on the metamorphic and multivalent nature of microtubule-associated proteins.

AI snapshot

Written from the paper’s full text.

TL;DR

Tau binds filamentous actin through multiple short helical segments in its repeat/proline-rich regions, using a dynamic multivalent mechanism to bundle F-actin and cross-link actin with microtubules. Phosphorylation by MARK2, including at S262, weakens this interaction and blocks bundling.

Key findings

  • Tau bundles F-actin; co-sedimentation showed ~63% of Tau remained in the supernatant, ~8% bound to single filaments, and ~29% associated with actin bundles. NBD-labeled F-actin binding gave a dissociation constant of 60 ± 10 nM; the Tau fragment K18 bound with a Kd of 110 ± 1 nM.
  • Tau binds the hydrophobic pocket between actin subdomains 1 and 3: cofilin displaced Tau from F-actin, and paramagnetic broadening with MTSSL-labeled C374 identified Tau repeat-domain residues near this pocket.
  • Transfer NOE experiments showed Tau(254–290) forms helical regions around residues ~261–268 and ~277–280 upon F-actin binding. Tau(254–268), containing only one helix, bound F-actin but did not bundle it, indicating at least two flexibly linked helices are required for bundling.
  • MARK2 phosphorylation at S262, S293, S305, S324, S356, and S416 attenuated Tau binding to F-actin and prevented F-actin bundling; phosphorylation of S262 in Tau(254–284) decreased affinity and bundling.

Methods

  • In vitro biophysics using human Tau 2N4R, synthetic Tau peptides, non-muscle human actin, and human cofilin: electron microscopy, co-sedimentation, and NBD-labeled F-actin fluorescence binding assays.
  • NMR spectroscopy: 2D 1H-15N HSQC, cofilin competition, paramagnetic relaxation enhancement with MTSSL-tagged F-actin, and transfer NOESY/TOCSY for peptide structure; structure calculations used CYANA/XPLOR-NIH, and docking used HADDOCK.
  • NMR samples included 20 µM 15N-labeled Tau with 30 µM F-actin for HSQC competition and 27 µM F-actin with 800 µM Tau peptide for NOESY experiments.

Limitations

  • Stated: the single-binding-site fit cannot exclude other stoichiometries; NOE restraints were insufficient to define a unique peptide conformation or the relative orientation of the two helical regions; ensemble NMR cannot distinguish simultaneous folding from individual site binding.
  • Stated: localization of phosphorylated Tau to actin-containing structures may involve additional actin-binding proteins, and future studies are needed to identify them.
  • Evident from the text: the structural and bundling conclusions come from in vitro reconstituted proteins and peptides, not cellular assays; some NMR experiments use high peptide concentrations and excess F-actin/cofilin, so direct physiological relevance is not established.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41467-017-02230-8

Cites

79 of 79 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

43 of 94 cited sources checked · 17 supported · 1 flagged · accuracy not yet measured

  • Interpretationreasoning

    The difference between the measured Tau/F-actin dissociation constant and the previously reported value is likely due to differences in ionic strength.

    “This is likely due of differences in ionic strength, because previous studies used phosphate buffer7, while we chose general actin assembly buffer.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [7] Elie, A. et al. Tau co-organizes dynamic microtubule and actin networks. Sci. Rep. 5, 9964 (2015). source

      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.

      Experimental — accuracy not yet measured
  • Findingown data

    Cross-peaks from Tau residues S262, N265, and T319 were strongly attenuated by F-actin.

    “According to the resonance assignment of Tau27, cross-peaks from residues such as S262, N265, and T319 were strongly attenuated.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [27] Mukrasch, M. D. et al. Structural polymorphism of 441-residue tau at single residue resolution. PLoS Biol. 7, e34 (2009). source
  • Findingown data

    The derived dissociation constant for Tau/F-actin is lower than the previously reported value of 241 ± 43 nM.

    “The derived dissociation constant is lower than a previously reported value of 241 ± 43 nM7.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [7] Elie, A. et al. Tau co-organizes dynamic microtubule and actin networks. Sci. Rep. 5, 9964 (2015). source
  • Premisecitation

    Binding of Tau and MAP2 to filamentous actin results in actin cross-linking and filament bundling.

    “Binding of Tau and MAP2 to filamentous actin results in actin cross-linking and filament bundling5, 6, 14, 22, 40–43.”
    Quote in the paperSubstantial claim3 of 8 sources checked
    • cites [5] Sattilaro, R. F. Interaction of microtubule-associated protein 2 with actin filaments. Biochemistry 25, 2003–2009 (1986). source
    • cites [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
    • 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). source

      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)

      Experimental — accuracy not yet measured
    • cites [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
    • cites [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
    • cites [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
    • 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). source

      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)

      Experimental — accuracy not yet measured
    • 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). source

      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)

      Experimental — accuracy not yet measured
  • Premisecitation

    Binding to F-actin can be retained while cross-linking activity is disrupted.

    “At the same time, binding to F-actin can be retained, but the cross-linking activity disrupted.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [5] Sattilaro, R. F. Interaction of microtubule-associated protein 2 with actin filaments. Biochemistry 25, 2003–2009 (1986). source
    • 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
  • Classified as probably not a substantial claim. 20
  • May combine two claims. 29

  • Classified as probably not a substantial claim.

    Premisecitation

    Interaction with filamentous actin plays an important role in dendritic spine morphology and postsynaptic reorganizations.

    “This is particularly the case for the interaction with filamentous actin, which plays an important role in dendritic spine morphology and postsynaptic reorganizations23.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [23] Hotulainen, P. & Hoogenraad, C. C. Actin in dendritic spines: connecting dynamics to function. J. Cell. Biol. 189, 619–629 (2010). source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Acetylation of Tau modulates actin polymerization and enhances synaptic dysfunction.

    “In addition, acetylation of Tau modulates actin polymerization and enhances synaptic dysfunction26.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [26] Tracy, T. E. et al. Acetylated Tau obstructs KIBRA-mediated signaling in synaptic plasticity and promotes tauopathy-related memory loss. Neuron 90, 245–260 (2016). source

  • Classified as probably not a substantial claim.

    Premisecitation

    Misfolding and aberrant accumulation of Tau is a pathological hallmark of Alzheimer's disease.

    “Misfolding and aberrant accumulation of Tau is a pathological hallmark of Alzheimer’s disease (AD)18, 19.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [18] Williams, D. R. Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tau. Intern. Med. J. 36, 652–660 (2006). source
    • cites [19] Fitzpatrick, A. W. P. et al. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 547, 185–190 (2017). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Tau occurs in six different isoforms in the human central nervous system.

    “Tau occurs in six different isoforms in the human central nervous system13, 14.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [13] Gustke, N., Trinczek, B., Biernat, J., Mandelkow, E. M. & Mandelkow, E. Domains of tau protein and interactions with microtubules. Biochemistry 33, 9511–9522 (1994). source
    • 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). source

      The Introduction (p. 717) describes tau isolated from adult brain as six related phosphopeptides and discusses several tau isoforms. It does not establish that six distinct isoforms occur in the human central nervous system; it says phosphatase treatment reduces the number of resolvable forms to four. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Tau isoforms differ in the number of N-terminal inserts and have either three or four imperfect repeats in their C-terminal half.

    “The Tau isoforms differ in the number of N-terminal inserts and have either three or four imperfect repeats in their C-terminal half15.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [15] Weingarten, M. D., Lockwood, A. H., Hwo, S. Y. & Kirschner, M. W. A protein factor essential for microtubule assembly. Proc. Natl Acad. Sci. USA 72, 1858–1862 (1975). source

      The Results and Discussion passages describe tau’s role in microtubule assembly, not the structures of tau isoforms. Searches for N-terminal inserts, three or four C-terminal repeats, and alternative splicing found no passage addressing the claim. Page numbers were not available in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The interaction of MAPs with actin is important for neurite outgrowth.

    “The interaction of MAPs with actin is important for neurite outgrowth11, 12.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [11] Knops, J. et al. Overexpression of tau in a nonneuronal cell induces long cellular processes. J. Cell. Biol. 114, 725–733 (1991). source

      The paper reports that tau expression induces long processes in nonneuronal Sf9 cells and, separately, that cytochalasin treatment produces short retraction processes by disrupting the actin network. The passages on process formation and cytochalasin do not address whether MAPs interact with actin or whether such an interaction is important for neurite outgrowth (searched: actin interaction, tau actin cytoskeleton). (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [12] Biernat, J. & Mandelkow, E. M. The development of cell processes induced by tau protein requires phosphorylation of serine 262 and 356 in the repeat domain and is inhibited by phosphorylation in the proline-rich domains. Mol. Biol. Cell. 10, 727–740 (1999). source

      The Introduction says MAPs regulate microtubules involved in neurite growth. In “A Model Relating tau Phosphorylation to Process Formation” (page unavailable), the paper says MAP interactions with cytoskeletal elements are important in process formation and separately mentions softening of the actin cortex. It does not specifically say that MAP–actin interactions are important for neurite outgrowth. (LLM, conf=0.81)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    More than one microtubule-binding repeat is believed to be required for bundling of filamentous actin.

    “Because a single repeat interacts with both monomeric and filamentous actin, but does not bundle actin filaments, more than one microtubule-binding repeat is believed to be required for bundling of filamentous actin (F-actin)17.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • 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

      The Results (page not provided) show that a peptide containing one tubulin-binding repeat binds G-actin and F-actin but does not bundle filaments. The authors suggest that bundling may require more than one actin-binding site; they do not establish that those sites must be multiple microtubule-binding repeats. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    A single microtubule-binding repeat interacts with both monomeric and filamentous actin but does not bundle actin filaments.

    “Because a single repeat interacts with both monomeric and filamentous actin, but does not bundle actin filaments, more than one microtubule-binding repeat is believed to be required for bundling of filamentous actin (F-actin)17.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • 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

  • May combine two claims.

    Premisecitation

    MAPs bundle actin filaments and cross-link the cellular cytoskeleton formed by microtubules and actin filaments.

    “In addition, MAPs bundle actin filaments and cross-link the cellular cytoskeleton formed by microtubules and actin filaments (Fig. 1a)3–10.”
    Quote in the paperSubstantial claim4 of 8 sources checked
    • cites [3] Yamauchi, P. S. & Purich, D. L. Microtubule-associated protein interactions with actin filaments: evidence for differential behavior of neuronal MAP-2 and tau in the presence of phosphatidyl-inositol. Biochem. Biophys. Res. Commun. 190, 710–715 (1993). source
    • cites [4] He, H. J. et al. The proline-rich domain of tau plays a role in interactions with actin. BMC Cell. Biol. 10, 81 (2009). source

      The Results and Discussion show that tau, a microtubule-associated protein, bundles F-actin. The Discussion describes tau and MAP2c as potential cross-linkers between microtubules and actin, but does not establish the citing sentence’s categorical claim that MAPs cross-link those networks in cells. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [5] Sattilaro, R. F. Interaction of microtubule-associated protein 2 with actin filaments. Biochemistry 25, 2003–2009 (1986). source
    • cites [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
    • cites [7] Elie, A. et al. Tau co-organizes dynamic microtubule and actin networks. Sci. Rep. 5, 9964 (2015). source
    • cites [8] Griffith, L. M. & Pollard, T. D. The interaction of actin filaments with microtubules and microtubule-associated proteins. J. Biol. Chem. 257, 9143–9151 (1982). source
    • 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). source

      The Discussion (page unavailable) says MAPs can interact with the actin cytoskeleton and may regulate microtubule bundling. It does not say MAPs bundle actin filaments or cross-link actin filaments with microtubules; the cited bundling concerns microtubules, not actin. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [10] Cunningham, C. C. et al. Microtubule-associated protein 2c reorganizes both microtubules and microfilaments into distinct cytological structures in an actin-binding protein-280-deficient melanoma cell line. J. Cell. Biol. 136, 845–857 (1997). source

      The Results section (‘MAP2c Causes Actin Gelation In Vitro’; page unavailable) reports that MAP2c forms actin bundles at higher concentrations or lower ionic strength. But the Discussion (‘In Vivo Functions of MAP2c’; page unavailable) explicitly says the data cannot determine whether MAP2c cross-links microtubules to actin filaments. The claim presents that cross-linking as established for MAPs generally. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Cofilin binds to F-actin with a Kd < 0.05 μM and results in disassembly of F-actin.

    “One of these binding partners is cofilin, a 21 kDa eukaryotic protein, which binds to F-actin with a K d < 0.05 µM33 and results in disassembly of F-actin34, 35.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [33] Bobkov, A. A. et al. Structural effects of cofilin on longitudinal contacts in F-actin. J. Mol. Biol. 323, 739–750 (2002). source
    • cites [34] Yonezawa, N. et al. Distribution among tissues and intracellular localization of cofilin, a 21kDa actin-binding protein. Cell. Struct. Funct. 12, 443–452 (1987). source

      The Cofilin section (page not provided) describes cofilin as a 21 kDa protein that binds F-actin, supporting that part of the statement attributed to this source. It does not give the cited F-actin Kd of <0.05 µM; its reported dissociation constant of 0.1–0.2 µM is for binding to monomeric actin. The separate disassembly statement carries other citations. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [35] Suarez, C. et al. Cofilin tunes the nucleotide state of actin filaments and severs at bare and decorated segment boundaries. Curr. Biol. 21, 862–868 (2011). source

      Citation 33 is attached to the Kd claim. In Results and Discussion (‘Bound ADF/cofilin dissociates slowly from actin filaments’; page unavailable), the paper reports rapid binding to bare actin filaments and high overall binding affinity, but gives no Kd below 0.05 µM. The disassembly clause is assigned to citations 34 and 35, not this source. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Actin contains five cysteine residues, and C374 incorporates more than 70% of spin labels during spin labeling reactions.

    “Although actin contains five cysteine residues, a number of studies has shown that the C-terminal C374, which is in close proximity to actin’s hydrophobic pocket (Fig. 2d), is most solvent exposed (Supplementary Fig. 4a, b) and incorporates more than 70% of spin labels during spin labeling reactions37–41.”
    Quote in the paperSubstantial claim1 of 5 sources checked
    • cites [37] Yasunaga, T. & Wakabayashi, T. Relocation of Cys374 of actin induced by labeling with fluorescent dyes. J. Biochem. 129, 201–204 (2001). source
    • cites [38] Kupi, T., Grof, P., Nyitrai, M. & Belagyi, J. The uncoupling of the effects of formins on the local and global dynamics of actin filaments. Biophys. J. 96, 2901–2911 (2009). source

      The section “Rotational motions in actin observed by spin labels” states that Cys-374 incorporated more than 70% of maleimide spin labels under the conditions used in the paper. Our copy does not state that actin has five cysteine residues, and the reported percentage is specific to those labeling conditions rather than spin labeling generally. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [39] Mossakowska, M., Belagyi, J. & Strzelecka-Golaszewska, H. An EPR study of the rotational dynamics of actins from striated and smooth muscle and their complexes with heavy meromyosin. Eur. J. Biochem. 175, 557–564 (1988). source
    • cites [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
    • cites [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

  • May combine two claims.

    Premisecitation

    Acetylation of Tau at K281, a residue located in an F-actin interacting helix of Tau, affects the interaction of Tau with actin and modulates Tau-mediated toxicity.

    “In addition to phosphorylation, acetylation of Tau at K281, a residues that is located in an F-actin interacting helix of Tau (Fig. 3d), affects the interaction of Tau with actin and modulate Tau-mediated toxicity26.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [26] Tracy, T. E. et al. Acetylated Tau obstructs KIBRA-mediated signaling in synaptic plasticity and promotes tauopathy-related memory loss. Neuron 90, 245–260 (2016). source

      The Results report that an acetylation-mimicking K274/K281 tau mutant interacted less with F-actin than wild-type tau; the Discussion links that mutant to synaptic dysfunction and memory deficits. The paper does not establish that K281 alone has these effects or describe K281 as located in an F-actin-interacting helix. Its evidence for altered tau–actin binding comes from the double mutant, not directly from acetylated tau. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Tau-induced remodeling of the actin cytoskeleton can cause plasma membrane blebbing.

    “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.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [57] Torres-Cruz, F. M. et al. Expression of Tau produces aberrant plasma membrane blebbing in glial cells through RhoA-ROCK-dependent F-actin remodeling. J. Alzheimers Dis. 52, 463–482 (2016). source

  • May combine two claims.

    Premisecitation

    Tau colocalizes with actin in differentiating PC12 cells, N2a cells and in the postsynaptic compartments of mature neurons.

    “Tau colocalizes with actin in differentiating PC12 cells68, N2a cells69 and in the postsynaptic compartments of mature neurons70.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [68] Yu, J. Z. & Rasenick, M. M. Tau associates with actin in differentiating PC12 cells. FASEB J. 20, 1452–1461 (2006). source
    • cites [69] Sontag, J. M., Nunbhakdi-Craig, V., Mitterhuber, M., Ogris, E. & Sontag, E. Regulation of protein phosphatase 2A methylation by LCMT1 and PME-1 plays a critical role in differentiation of neuroblastoma cells. J. Neurochem. 115, 1455–1465 (2010). source

      The Results (page unavailable) report tau-positive processes and altered F-actin organization in differentiating N2a cells. They do not report that tau and actin colocalize; the cited paper supports their presence in these cells, but not the specific spatial relationship attributed to it. Citation 69 is attached only to the N2a-cell portion of the sentence. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [70] Thies, E. & Mandelkow, E. M. Missorting of tau in neurons causes degeneration of synapses that can be rescued by the kinase MARK2/Par-1. J. Neurosci. 27, 2896–2907 (2007). source

      For citation 70, the 'Missorting of tau and effects on synapses' section (Fig. 1; page not provided) reports that F-actin fills postsynaptic spine heads and that expressed tau enters those spine heads in hippocampal neurons with mature synapses. The claim omits the crucial condition: tau was experimentally expressed and missorted; in untransfected neurons, the paper reports tau only in axons. Citations 68 and 69, attached to the PC12 and N2a claims, are not assessed here. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    The hexapeptide 275VQIINK280 populates extended structure in solution, is found in cross-β structure in amyloid fibrils, but folds into helical structure in complex with F-actin.

    “The hexapeptide populates extended structure in solution27, is found in cross-β structure in amyloid fibrils63, but folds into helical structure in complex with F-actin (Fig. 3d).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [27] Mukrasch, M. D. et al. Structural polymorphism of 441-residue tau at single residue resolution. PLoS Biol. 7, e34 (2009). source
    • cites [63] Andronesi, O. C. et al. Characterization of Alzheimer’s-like paired helical filaments from the core domain of tau protein using solid-state NMR spectroscopy. J. Am. Chem. Soc. 130, 5922–5928 (2008). source

  • May combine two claims.

    Premisecitation

    Phosphorylated Tau is recruited to actin-cofilin rods, which might lead to neuropil threads.

    “In addition, phosphorylated Tau is recruited to actin-cofilin rods, which might lead to neuropil threads56.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [56] Whiteman, I. T. et al. Activated actin-depolymerizing factor/cofilin sequesters phosphorylated microtubule-associated protein during the assembly of Alzheimer-like neuritic cytoskeletal striations. J. Neurosci. 29, 12994–13005 (2009). source

  • May combine two claims.

    Findingown data

    STRIDE identifies α-helix for residues 261-268 and 3-10 helix for residues 277-280 in the lowest energy conformation of Tau(254-290).

    “Analysis of secondary structure in the lowest energy conformation using STRIDE47, identifies α-helix for residues 261–268 and 3–10 helix for residues 277–280.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [47] Heinig, M. & Frishman, D. STRIDE: a web server for secondary structure assignment from known atomic coordinates of proteins. Nucleic Acids Res. 32, W500–W502 (2004). source

  • May combine two claims.

    Interpretationcitation

    The N-terminal halves of each of Tau's four 18-residue aminoacid repeats bind to F-actin's hydrophobic pocket and fold into helical structure.

    “In addition, the N-terminal halves of each of Tau’s four 18-residue aminoacid repeats64 bind to F-actin’s hydrophobic pocket and fold into helical structure (Fig. 3c; Supplementary Figs. 12 and 14).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [64] Goode, B. L. & Feinstein, S. C. Identification of a novel microtubule binding and assembly domain in the developmentally regulated inter-repeat region of tau. J. Cell. Biol. 124, 769–782 (1994). source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The interaction of Tau with actin is important for neurite outgrowth and synaptic dysfunction.

    “The interaction of Tau with actin is important for neurite outgrowth and synaptic dysfunction11, 12, 22.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [11] Knops, J. et al. Overexpression of tau in a nonneuronal cell induces long cellular processes. J. Cell. Biol. 114, 725–733 (1991). source

      The Introduction (p. 725) links tau to neurite elongation, and the discussion reports that tau-expressing Sf9 cells developed long processes. The paper does not establish that tau’s interaction with actin drives outgrowth or synaptic dysfunction; it says synaptic vesicles were not observed in those processes. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [12] Biernat, J. & Mandelkow, E. M. The development of cell processes induced by tau protein requires phosphorylation of serine 262 and 356 in the repeat domain and is inhibited by phosphorylation in the proline-rich domains. Mol. Biol. Cell. 10, 727–740 (1999). source

      The introduction and 'A Model Relating tau Phosphorylation to Process Formation' (page unavailable) link tau to neurite or cell-process outgrowth and mention softening of the actin cortex before a process forms. They do not establish that a tau–actin interaction drives outgrowth, and they do not address synaptic dysfunction. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [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

  • May combine two claims.

    Premisecitation

    Cys374 of actin is solvent exposed and can be labeled with the spin label MTSSL.

    “Cys374 of actin is solvent exposed and can be labeled with the spin label MTSSL37–41.”
    Quote in the paperSubstantial claim1 of 5 sources checked
    • cites [37] Yasunaga, T. & Wakabayashi, T. Relocation of Cys374 of actin induced by labeling with fluorescent dyes. J. Biochem. 129, 201–204 (2001). source
    • cites [38] Kupi, T., Grof, P., Nyitrai, M. & Belagyi, J. The uncoupling of the effects of formins on the local and global dynamics of actin filaments. Biophys. J. 96, 2901–2911 (2009). source

      The Introduction and “Rotational motions in actin observed by spin labels” report that a spin label attaches to Cys-374 and that this site incorporated more than 70% of the labels under the experimental conditions. This supports its accessibility for labeling, but the paper uses maleimide spin label (MSL), not MTSSL, and does not explicitly describe Cys-374 as solvent exposed. Page numbers were not available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [39] Mossakowska, M., Belagyi, J. & Strzelecka-Golaszewska, H. An EPR study of the rotational dynamics of actins from striated and smooth muscle and their complexes with heavy meromyosin. Eur. J. Biochem. 175, 557–564 (1988). source
    • cites [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
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Pathogenic forms of Tau have been connected to the formation of actin-rich rods, which were found to induce neurodegeneration in Drosophila neurons.

    “Pathogenic forms of Tau have been connected to the formation of actin-rich rods56, which were found to induce neurodegeneration in Drosophila neurons22.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [56] Whiteman, I. T. et al. Activated actin-depolymerizing factor/cofilin sequesters phosphorylated microtubule-associated protein during the assembly of Alzheimer-like neuritic cytoskeletal striations. J. Neurosci. 29, 12994–13005 (2009). source
    • cites [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

  • May combine two claims.

    Premisecitation

    A C-terminal fragment and a peptide corresponding to the second microtubule-binding repeat bind actin but are incapable of mediating actin cross-linking.

    “For example, a C-terminal fragment and a peptide corresponding to the second microtubule-binding repeat bind actin, but are incapable of mediating actin cross-linking5, 17.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [5] Sattilaro, R. F. Interaction of microtubule-associated protein 2 with actin filaments. Biochemistry 25, 2003–2009 (1986). source
    • 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

      The Results report that the synthetic tau peptide binds G-actin and F-actin but does not bundle actin filaments. The Introduction and Discussion describe it as corresponding to one tubulin-binding repeat, without identifying it as the second. They report that a 32 kDa MAP-2 fragment binds actin, but do not establish that this C-terminal fragment cannot cross-link actin. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Tau binds with high affinity to filamentous actin, resulting in F-actin bundling.

    “In agreement with previous findings, we show that Tau binds with high-affinity to filamentous actin, resulting in F-actin bundling (Fig. 1b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Addition of an equimolar concentration of Tau causes bundling of F-actin, although some single filaments remain.

    “Addition of an equimolar concentration of Tau caused bundling of F-actin (Fig. 1b), although some single filaments remained.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Tau and cofilin helices are well conserved, but the directionality of their polypeptide chain is inverted.

    “Tau and cofilin helices is well conserved, but the directionality of their polypeptide chain is inverted (Fig. 3e, f).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Haddock clustered 192 complex structures in four clusters, representing 96.0% of the water-refined Haddock models.

    “Haddock clustered 192 complex structures in four clusters, representing 96.0% of the water-refined Haddock models.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Both the proline-rich region and the microtubule-binding repeats contribute to the Tau/F-actin interaction.

    “Both the proline-rich region and the microtubule-binding repeats contribute to the interaction (Figs. 1e, f).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Docking of experimentally determined Tau helices to the F-actin surface together with sequence alignment showed that the overall position of the interacting Tau and cofilin helices is well conserved, but the directionality of their polypeptide chain is inverted.

    “Docking of experimentally determined Tau helices to the F-actin surface together with sequence alignment showed that the overall position of the interacting Tau and cofilin helices is well conserved, but the directionality of their polypeptide chain is inverted (Fig. 3e, f).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    MAPs such as Tau belong to the class of intrinsically disordered proteins, which do not fold into a stable three-dimensional structure.

    “MAPs such as Tau belong to the class of intrinsically disordered proteins, which do not fold into a stable three-dimensional structure28.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Dyson, H. J. & Wright, P. E. Intrinsically unstructured proteins and their functions. Nat. Rev. Mol. Cell. Biol. 6, 197–208 (2005). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Proteins from the MAP2 family bind to actin filaments through their repeat domain.

    “Proteins from the MAP2 family also bind to actin filaments through their repeat domain8.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Griffith, L. M. & Pollard, T. D. The interaction of actin filaments with microtubules and microtubule-associated proteins. J. Biol. Chem. 257, 9143–9151 (1982). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Microtubule-associated proteins bind to stabilize and promote assembly of microtubules.

    “Microtubule-associated proteins (MAPs) bind to stabilize and promote assembly of microtubules1, 2.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Mandelkow, E. & Mandelkow, E. M. Microtubules and microtubule-associated proteins. Curr. Opin. Cell. Biol. 7, 72–81 (1995). source
    • cites [2] Lee, G. Non-motor microtubule-associated proteins. Curr. Opin. Cell. Biol. 5, 88–94 (1993). source

  • Classified as probably not a substantial claim.

    Premisecitation

    The binding site of cofilin on F-actin is highly similar to its binding site on G-actin.

    “Cryo-electron microscopy further showed that the binding site of cofilin on F-actin is highly similar to its binding site on G-actin (Fig. 2a)32.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Carlier, M. F. & Pantaloni, D. Control of actin dynamics in cell motility. J. Mol. Biol. 269, 459–467 (1997). source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The tight connection between microtubules and actin drives the guided extension of axons during neuronal development as well as the formation and activity of synapses in mature neurons.

    “Moreover the tight connection between microtubules and actin drives the guided extension of axons during neuronal development as well as the formation and activity of synapses in mature neurons67.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Hoogenraad, C. C. & Bradke, F. Control of neuronal polarity and plasticity--a renaissance for microtubules? Trends Cell. Biol. 19, 669–676 (2009). source

  • May combine two claims.

    Interpretationcitation

    The conformations induced in Tau upon binding to F-actin and microtubules are very different, because F-actin interaction is connected to helix formation, while short Tau regions fold into a hairpin-like structure in complex with microtubules.

    “Notably, the conformations that are induced in Tau upon binding to F-actin and microtubules are very different, because F-actin interaction is connected to helix formation (Fig. 3), while short Tau regions fold into a hairpin-like structure in complex with microtubules46.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Kadavath, H. et al. Folding of the tau protein on microtubules. Angew. Chem. Int. Ed. Engl. 54, 10347–10351 (2015). source

  • May combine two claims.

    Interpretationreasoning

    Tau utilizes a structural mechanism for binding to actin filaments, which is used by many actin-binding proteins, but allows a highly dynamic and multivalent interaction with both actin filaments and microtubules.

    “We showed that Tau utilizes a structural mechanism for binding to actin filaments, which is used by many actin-binding proteins, but allows a highly dynamic and multivalent interaction with both actin filaments and microtubules.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    These data support a role for Tau as regulator of microtubules and actin and suggest its potential role as linker between both cytoskeletons.

    “These data support a role for Tau as regulator of microtubules and actin and suggests its potential role as linker between the both cytoskeletons.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The F-actin-interacting Tau residues are separated from each other by flexible linkers, which enable a high degree of dynamics and multivalency in the Tau/F-actin interaction.

    “The F-actin-interacting Tau residues are separated from each other by flexible linkers, which enable a high degree of dynamics and multivalency in the Tau/F-actin interaction.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The interaction between actin filaments and microtubules is important for cellular processes including cell division, vesicle and organelle transport, axonal growth and migration.

    “The interaction between actin filaments and microtubules is important for cellular processes including cell division, vesicle and organelle transport, axonal growth and migration66.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Rodriguez, O. C. et al. Conserved microtubule-actin interactions in cell movement and morphogenesis. Nat. Cell. Biol. 5, 599–609 (2003). source

  • May combine two claims.

    Interpretationown data

    Bundling of filamentous actin and cross-linking of the cellular cytoskeleton depend on the metamorphic and multivalent nature of microtubule-associated proteins.

    “Taken together the data demonstrate that bundling of filamentous actin and cross-linking of the cellular cytoskeleton depend on the metamorphic and multivalent nature of microtubule-associated proteins.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Tau undergoes several post-translational modifications that influence its function, aggregation and toxicity.

    “Tau undergoes several post-translational modifications that influence its function, aggregation and toxicity73.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Gong, C. X., Liu, F., Grundke-Iqbal, I. & Iqbal, K. Post-translational modifications of tau protein in Alzheimer’s disease. J. Neural Transm. 112, 813–838 (2005). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Tau is hyperphosphorylated in the brains of patients with Alzheimer's disease.

    “An important post-translational modification is phosphorylation, because Tau is hyperphosphorylated in the brains of patients with Alzheimer’s disease74.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] Bancher, C. et al. Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer’s disease. Brain Res. 477, 90–99 (1989). source

  • May combine two claims.

    Interpretationown data

    Optimal sequence alignment of cofilin and Tau was achieved when the sequence of Tau was inverted, suggesting an inverted orientation of its recognition helix when compared to cofilin.

    “Optimal sequence alignment was achieved, when the sequence of Tau was inverted (Fig. 3f), suggesting an inverted orientation of its recognition helix when compared to cofilin (Fig. 3e; Supplementary Fig. 9).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Phosphorylation of Tau at KXGS motifs fosters the interaction with actin-containing structures, but attenuates the direct interaction of Tau with microtubules and F-actin.

    “Thus, phosphorylation of Tau at KXGS motifs fosters the interaction with actin-containing structures, but attenuates the direct interaction of Tau with microtubules and F-actin.”
    Quote in the paperSubstantial claim
43 of 43

  • The paper relies on this without support.

    Little is known about the molecular nature of the Tau/F-actin complex, the involved binding sites, the mechanism of F-actin bundling, and the MAP-driven process of cross-linking of microtubules and actin filaments.

    “Little is known, however, about the molecular nature of the Tau/F-actin complex, about the involved binding sites, the mechanism of F-actin bundling and the MAP-driven process of cross-linking of microtubules and actin filaments.”

  • The paper relies on this without support.

    Intrinsically disordered proteins often contain multiple binding sites with each binding site only providing low affinity for a target protein.

    “In addition, intrinsically disordered proteins often contain multiple binding sites with each binding site only providing low affinity for a target protein.”

  • The paper relies on this without support.

    A single-binding site model adequately describes the Tau/F-actin binding data for determining the dissociation constant.

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

  • The paper relies on this without support.

    The lowest energy conformation of Tau(254–290) is representative of its F-actin-bound structure for docking.

    “To this end, the lowest energy conformation of Tau(254–290) was docked to the solvent-exposed, hydrophobic pocket of actin within the actin filament structure using the software Haddock48.”

  • The paper relies on this without support.

    The structure of cofilin-decorated F-actin is a valid template for modeling the Tau/F-actin binding site.

    “To derive a structural model for the Tau/F-actin binding site, we integrated the information that was obtained in the current work (Figs. 1–3) with the 3D structure of cofilin-decorated F-actin (Fig. 2a).”

  • The paper relies on this without support.

    The molecular mechanisms regulating the crosstalk between actin filaments and microtubules are poorly understood.

    “However the molecular mechanisms regulating this cytoskeletal crosstalk are poorly understood.”

  • The paper relies on this without support.

    The repeat domain of Tau contains an excess positive charge.

    “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.”
7 of 7

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.

  • Different F-actin concentrations reported for the fluorescence binding assay

    Minor

    The Results describe the fluorescence assay as using 0.2 μM NBD-labeled F-actin, while the Methods specify 0.25 μM for the same assay.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. He, H. J. et al. The proline-rich domain of tau plays a role in interactions with actin. BMC Cell Biol. 10, 81 (2009). · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Cabrales Fontela, Y., Kadavath, H., Biernat, J., Riedel, D., Mandelkow, E., & Zweckstetter, M.
Affiliations
  • German Center for Neurodegenerative Diseases (DE)
  • Max Planck Institute for Biophysical Chemistry (DE)
Corresponding author
Zweckstetter, Markus
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-12-07
Volume
8
Issue
1
Pages
1981-1981
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-017-02230-8
PMC
PMC5719408
OpenAlex
W2771232440
Cited by
148
References
79
Citations by year
2026: 9 · 2025: 20 · 2024: 11 · 2023: 14 · 2022: 18 · 2021: 23 · 2020: 22 · 2019: 22 · 2018: 9
FWCI
10.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion, cc-by)
  • MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Max Planck Digital Library (submittedVersion, other-oa)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
  • DZNE Pub (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
Keywords
tau protein, F-actin, microtubules, actin bundling, multivalent binding, microtubule-associated proteins, cytoskeleton, Alzheimer's disease, synaptic dysfunction
MeSH terms
Alzheimer Disease, Humans, Actin Cytoskeleton, Microtubule-Associated Proteins, Microtubules, Phosphorylation, Serine, tau Proteins, Actin Depolymerizing Factors, Protein Interaction Domains and Motifs, Hydrophobic and Hydrophilic Interactions, Molecular Docking Simulation

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-11-02.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-02.

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