The stability and dynamics of cytoskeleton in brain nerve cells are regulated by microtubule associated proteins (MAPs), tau and MAP2. Both proteins are intrinsically disordered and involved in multiple molecular interactions important for normal physiology and pathology of chronic neurodegenerative diseases. Nuclear magnetic resonance and cryo-electron microscopy recently revealed propensities of MAPs to form transient local structures and long-range contacts in the free state, and conformations adopted in complexes with microtubules and filamentous actin, as well as in pathological aggregates. In this paper, we compare the longest, 441-residue brain isoform of tau (tau40), and a 467-residue isoform of MAP2, known as MAP2c. For both molecules, we present transient structural motifs revealed by conformational analysis of experimental data obtained for free soluble forms of the proteins. We show that many of the short sequence motifs that exhibit transient structural features are linked to functional properties, manifested by specific interactions. The transient structural motifs can be therefore classified as molecular recognition elements of tau40 and MAP2c. Their interactions are further regulated by post-translational modifications, in particular phosphorylation. The structure-function analysis also explains differences between biological activities of tau40 and MAP2c.

Axon Neuroscience R and D Services SE Dvořákovo nábrežie 10 811 02 Bratislava Slovakia

Central European Institute of Technology Masaryk University Kamenice 5 625 00 Brno Czech Republic

Department of NMR Based Structural Biology Max Planck Institute for Biophysical Chemistry Am Fassberg 11 37077 Göttingen Germany

Faculty of Science National Centre for Biomolecular Research Masaryk University Kamenice 5 625 00 Brno Czech Republic

German Center for Neurodegenerative Diseases Von Siebold Str 3a 37075 Göttingen Germany

Institute of Neuroimmunology Slovak Academy of Sciences Dúbravská cesta 9 845 10 Bratislava Slovakia

University Grenoble Alps CEA CNRS 38000 Grenoble France

Zobrazit více v PubMed

Amos L.A., Schlieper D. Microtubules and MAPs. Adv. Protein Chem. 2005;71:257–298. PubMed

Dehmelt L., Halpain S. The MAP2/Tau family of microtubule-associated proteins. Genome Biol. 2004;6:204. doi: 10.1186/gb-2004-6-1-204. PubMed DOI PMC

Arendt T., Stieler J.T., Holzer M. Tau and tauopathies. Brain Res. Bull. 2016;126:238–292. doi: 10.1016/j.brainresbull.2016.08.018. PubMed DOI

Caillet-Boudin M.L., Buée L., Sergeant N., Lefebvre B. Regulation of human MAPT gene expression. Mol. Neurodegener. 2015;10:28. doi: 10.1186/s13024-015-0025-8. PubMed DOI PMC

Sánchez C., Díaz-Nido J., Avila J. Phosphorylation of microtubule-associated protein 2 (MAP2) and its relevance for the regulation of the neuronal cytoskeleton function. Prog. Neurobiol. 2000;61:133–168. doi: 10.1016/S0301-0082(99)00046-5. PubMed DOI

Kanai Y., Hirokawa N. Sorting mechanisms of Tau and MAP2 in neurons: Suppressed axonal transit of MAP2 and locally regulated microtubule binding. Neuron. 1995;14:421–432. doi: 10.1016/0896-6273(95)90298-8. PubMed DOI

Chen J., Kanai Y., Cowan N.J., Hirokawa N. Projection domains of MAP2 and tau determine spacings between microtubules in dendrites and axons. Nature. 1992;360:674–677. doi: 10.1038/360674a0. PubMed DOI

Rosenberg K.J., Ross J.L., Feinstein H.E., Feinstein S.C., Israelachvili J. Complementary dimerization of microtubule-associated tau protein: Implications for microtubule bundling and tau-mediated pathogenesis. Proc. Natl. Acad. Sci. USA. 2008;105:7445–7450. doi: 10.1073/pnas.0802036105. PubMed DOI PMC

Chung P.J., Choi M.C., Miller H.P., Feinstein H.E., Raviv U., Li Y., Wilson L., Feinstein S.C., Safinya C.R. Direct force measurements reveal that protein Tau confers short-range attractions and isoform-dependent steric stabilization to microtubules. Proc. Natl. Acad. Sci. USA. 2015;112:E6416–E6425. doi: 10.1073/pnas.1513172112. PubMed DOI PMC

Cabrales Fontela Y., Kadavath H., Biernat J., Riedel D., Mandelkow E., Zweckstetter M. Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau. Nat. Commun. 2017;8:1981. doi: 10.1038/s41467-017-02230-8. PubMed DOI PMC

Elie A., Prezel E., Guérin C., Denarier E., Ramirez-Rios S., Serre L., Andrieux A., Fourest-Lieuvin A., Blanchoin L., Arnal I. Tau co-organizes dynamic microtubule and actin networks. Sci. Rep. 2015;5:9964. doi: 10.1038/srep09964. PubMed DOI PMC

Goode B.L., Chau M., Denis P.E., Feinstein S.C. Structural and functional differences between 3-repeat and 4-repeat tau isoforms: Implications for normal tau function and the onset of neurodegenerative disease. J. Biol. Chem. 2000;275:38182–38189. doi: 10.1074/jbc.M007489200. PubMed DOI

Harada A., Oguchi K., Okabe S., Kuno J., Terada S., Ohshima T., Sato-Yoshitake R., Takei Y., Noda T., Hirokawa N. Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature. 1994;369:488–491. doi: 10.1038/369488a0. PubMed DOI

Teng J., Takei Y., Harada A., Nakata T., Chen J., Hirokawa N. Synergistic effects of MAP2 and MAP1B knockout in neuronal migration, dendritic outgrowth, and microtubule organization. J. Cell Biol. 2001;155:65–76. doi: 10.1083/jcb.200106025. PubMed DOI PMC

Takei Y., Teng J., Harada A., Hirokawa N. Defects in Axonal Elongation and Neuronal Migration in Mice with Disrupted tau and map1b Genes. J. Cell Biol. 2000;150:989–1000. doi: 10.1083/jcb.150.5.989. PubMed DOI PMC

Mukaetova-Ladinska E.B., Xuereb J.H., Garcia-Sierra F., Hurt J., Gertz H.J., Hills R., Brayne C., Huppert F.A., Paykel E.S., McGee M.A., et al. Lewy body variant of Alzheimer’s disease: Selective neocortical loss of t-SNARE proteins and loss of MAP2 and α-Synuclein in medial temporal lobe. Sci. World J. 2009;9:1463–1475. doi: 10.1100/tsw.2009.151. PubMed DOI PMC

D’Andrea M.R., Ilyin S., Plata-Salaman C.R. Abnormal patterns of microtubule-associated protein-2 (MAP-2) immunolabeling in neuronal nuclei and Lewy bodies in Parkinson’s disease substantia nigra brain tissues. Neurosci. Lett. 2001;306:137–140. doi: 10.1016/S0304-3940(01)01811-0. PubMed DOI

Cabrera J.R., Lucas J.J. MAP2 Splicing is Altered in Huntington’s Disease. Brain Pathol. 2016;27:181–189. doi: 10.1111/bpa.12387. PubMed DOI PMC

Bianchi M., Baulieu E.E. 3β-Methoxy-pregnenolone (MAP4343) as an innovative therapeutic approach for depressive disorders. Proc. Natl. Acad. Sci. USA. 2012;109:1713–1718. doi: 10.1073/pnas.1121485109. PubMed DOI PMC

Goedert M. Tau filaments in neurodegenerative diseases. FEBS Lett. 2018;592:2383–2391. doi: 10.1002/1873-3468.13108. PubMed DOI

Congdon E.E., Sigurdsson E.M. Tau-targeting therapies for Alzheimer disease. Nat. Rev. Neurol. 2018;14:399–415. doi: 10.1038/s41582-018-0013-z. PubMed DOI PMC

Novak P., Cehlar O., Skrabana R., Novak M. Tau Conformation as a Target for Disease-Modifying Therapy: The Role of Truncation. J. Alzheimers Dis. 2018;64:S535–S546. doi: 10.3233/JAD-179942. PubMed DOI

Jadhav S., Avila J., Schöll M., Kovacs G.G., Kövari E., Skrabana R., Evans L.D., Kontsekova E., Malawska B., de Silva R., et al. A walk through tau therapeutic strategies. Acta Neuropathol. Commun. 2019;7:22. doi: 10.1186/s40478-019-0664-z. PubMed DOI PMC

Fitzpatrick A.W.P., Falcon B., He S., Murzin A.G., Murshudov G., Garringer H.J., Crowther R.A., Ghetti B., Goedert M., Scheres S.H.W. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature. 2017;547:185–190. doi: 10.1038/nature23002. PubMed DOI PMC

DeTure M.A., Di Noto L., Purich D.L. In vitro assembly of Alzheimer-like filaments: How a small cluster of charged residues in Tau and MAP2 controls filament morphology. J. Biol. Chem. 2002;277:34755–34759. doi: 10.1074/jbc.M201201200. PubMed DOI

Xie C., Soeda Y., Shinzaki Y., In Y., Tomoo K., Ihara Y., Miyasaka T. Identification of key amino acids responsible for the distinct aggregation properties of microtubule-associated protein 2 and tau. J. Neurochem. 2015;135:19–26. doi: 10.1111/jnc.13228. PubMed DOI PMC

Wang Y., Mandelkow E. Tau in physiology and pathology. Nat. Rev. Nerocsi. 2016;17:5–21. doi: 10.1038/nrn.2015.1. PubMed DOI

Sánchez C., Pérez M., Avila J. GSK3β-mediated phosphorylation of the microtubule-associated protein 2C (MAP2C) prevents microtubule bundling. Eur. J. Cell Biol. 2000;79:252–260. doi: 10.1078/S0171-9335(04)70028-X. PubMed DOI

Fischer D., Mukrasch M.D., Biernat J., Bibow S., Blackledge M., Griesinger C., Mandelkow E., Zweckstetter M. Conformational Changes Specific for Pseudophosphorylation at Serine 262 Selectively Impair Binding of Tau to Microtubules. Biochemistry. 2009;48:10047–10055. doi: 10.1021/bi901090m. PubMed DOI

Schwalbe M., Biernat J., Bibow S., Ozenne V., Jensen M.R., Kadavath H., Blackledge M., Mandelkow E., Zweckstetter M. Phosphorylation of human tau protein by microtubule affinity-regulating kinase 2. Biochemistry. 2013;52:9068–9079. doi: 10.1021/bi401266n. PubMed DOI

Schwalbe M., Kadavath H., Biernat J., Ozenne V., Blackledge M., Mandelkow E., Zweckstetter M. Structural Impact of Tau Phosphorylation at Threonine 231. Structure. 2015;23:1448–1458. doi: 10.1016/j.str.2015.06.002. PubMed DOI

Tholey A., Lindemann A., Kinzel V., Reed J. Direct effects of phosphorylation on the preferred backbone conformation of peptides: A nuclear magnetic resonance study. Biophys. J. 1999;76:76–87. doi: 10.1016/S0006-3495(99)77179-1. PubMed DOI PMC

Newberry R.W., Raines R.T. The n→π* Interaction. Acc. Chem. Res. 2017;50:1838–1846. doi: 10.1021/acs.accounts.7b00121. PubMed DOI PMC

Bielska A.A., Zondlo N.J. Hyperphosphorylation of Tau Induces Local Polyproline II Helix. Biochemistry. 2006;45:5527–5537. doi: 10.1021/bi052662c. PubMed DOI

Martin L., Latypova X., Wilson C.M., Magnaudeix A., Perrin M.L., Yardin C., Terro F. Tau protein kinases: Involvement in Alzheimer’s disease. Ageing Res. Rev. 2013;12:289–309. doi: 10.1016/j.arr.2012.06.003. PubMed DOI

Lebouvier T., Scales T.M.E., Williamson R., Noble W., Duyckaerts C., Hanger D.P., Reynolds C.H., Anderton B.H., Derkinderen P. The Microtubule-Associated Protein Tau is Also Phosphorylated on Tyrosine. J. Alzheimers Dis. 2009;18:1–9. doi: 10.3233/JAD-2009-1116. PubMed DOI

Tremblay M.A., Acker C.M., Davies P. Tau phosphorylated at tyrosine 394 is found in Alzheimer’s disease tangles and can be a product of the abl-related kinase, Arg. J. Alzheimers Dis. 2010;19:721–733. doi: 10.3233/JAD-2010-1271. PubMed DOI PMC

Mukrasch M.D., Bibow S., Korukottu J., Jeganathan S., Biernat J., Griesinger C., Mandelkow E., Zweckstetter M. Structural polymorphism of 441-residue tau at single residue resolution. PLoS Biol. 2009;7:e34. doi: 10.1371/journal.pbio.1000034. PubMed DOI PMC

Schwalbe M., Ozenne V., Bibow S., Jaremko M., Jaremko L., Gajda M., Jensen M.R., Biernat J., Becker S., Mandelkow E., et al. Predictive Atomic Resolution Descriptions of Intrinsically Disordered hTau40 and α-Synuclein in Solution from NMR and Small Angle Scattering. Structure. 2014;22:238–249. doi: 10.1016/j.str.2013.10.020. PubMed DOI

Jansen S., Melková K., Trošanová Z., Hanáková K., Zachrdla M., Nováček J., Župa E., Zdráhal Z., Hritz J., Žídek L. Quantitative mapping of microtubule-associated protein 2c (MAP2c) phosphorylation and regulatory protein 14-3-3ζ-binding sites reveals key differences between MAP2c and its homolog Tau. J. Biol. Chem. 2017;292:6715–6727. doi: 10.1074/jbc.M116.771097. PubMed DOI PMC

Kadavath H., Jaremko M., Jaremko Ł., Biernat J., Mandelkow E., Zweckstetter M. Folding of the Tau Protein on Microtubules. Angew. Chem. Int. Ed. 2015;54:10347–10351. doi: 10.1002/anie.201501714. PubMed DOI

Kadavath H., Hofele R.V., Biernat J., Kumar S., Tepper K., Urlaub H., Mandelkow E., Zweckstetter M. Tau stabilizes microtubules by binding at the interface between tubulin heterodimers. Proc. Natl. Acad. Sci. USA. 2015;112:7501–7506. doi: 10.1073/pnas.1504081112. PubMed DOI PMC

Kellogg E.H., Hejab N.M.A., Poepsel S., Downing K.H., DiMaio F., Nogales E. Near-atomic model of microtubule-tau interactions. Science. 2018;360:1242–1246. doi: 10.1126/science.aat1780. PubMed DOI PMC

Bibow S., Mukrasch M.D., Chinnathambi S., Biernat J., Griesinger C., Mandelkow E., Zweckstetter M. The dynamic structure of filamentous Tau. Angew. Chem. Int. Ed. 2011;50:11520–11524. doi: 10.1002/anie.201105493. PubMed DOI

Sündermann F., Fernandez M.P., Morgan R.O. An evolutionary roadmap to the microtubule-associated protein MAP Tau. BMC Genom. 2016;17:264. doi: 10.1186/s12864-016-2590-9. PubMed DOI PMC

Smet C., Leroy A., Sillen A., Wieruszeski J.M., Landrieu I., Lippens G. Accepting its Random Coil Nature Allows a Partial NMR Assignment of the Neuronal Tau Protein. ChemBioChem. 2004;5:1639–1646. doi: 10.1002/cbic.200400145. PubMed DOI

Lippens G., Wieruszeski J.M., Leroy A., Smet C., Sillen A., Buée L., Landrieu I. Proline-Directed Random-Coil Chemical Shift Values as a Tool for the NMR Assignment of the Tau Phosphorylation Sites. ChemBioChem. 2004;5:73–78. doi: 10.1002/cbic.200300763. PubMed DOI

Mukrasch M.D., Biernat J., von Bergen M., Griesinger C., Mandelkow E., Zweckstetter M. Sites of tau important for aggregation populate β-structure and bind to microtubules and polyanions. J. Biol. Chem. 2005;280:24978–24986. doi: 10.1074/jbc.M501565200. PubMed DOI

Mukrasch M.D., von Bergen M., Biernat J., Fischer D., Griesinger C., Mandelkow E., Zweckstetter M. The “jaws” of the tau-microtubule interaction. J. Biol. Chem. 2007;282:12230–12239. doi: 10.1074/jbc.M607159200. PubMed DOI

Verdegem D., Dijkstra K., Hanoulle X., Lippens G. Graphical interpretation of Boolean operators for protein NMR assignments. J. Biomol. NMR. 2008;42:11–21. doi: 10.1007/s10858-008-9262-2. PubMed DOI

Sibille N., Hanoulle X., Fanny B., Dries V., Isabelle L., Jean-Michel W., Guy L. Selective backbone labelling of ILV methyl labelled proteins. J. Biomol. NMR. 2009;43:219–227. doi: 10.1007/s10858-009-9307-1. PubMed DOI

Lopez J., Ahuja P., Gerard M., Wieruszeski J.M., Lippens G. A new strategy for sequential assignment of intrinsically unstructured proteins based on 15N single isotope labelling. J. Magn. Reson. 2013;236:1–6. doi: 10.1016/j.jmr.2013.07.007. PubMed DOI

Narayanan R.L., Dürr U.H.N., Bibow S., Biernat J., Mandelkow E., Zweckstetter M. Automatic Assignment of the Intrinsically Disordered Protein Tau with 441-Residues. J. Am. Chem. Soc. 2010;132:11906–11907. doi: 10.1021/ja105657f. PubMed DOI

Harbison N.W., Bhattacharya S., Eliezer D. Assigning Backbone NMR Resonances for Full Length Tau Isoforms: Efficient Compromise between Manual Assignments and Reduced Dimensionality. PLoS ONE. 2012;7:e34679. doi: 10.1371/journal.pone.0034679. PubMed DOI PMC

Nováček J., Janda L., Dopitová R., Žídek L., Sklenář V. Efficient protocol for backbone and side-chain assignments of large, intrinsically disordered proteins: Transient secondary structure analysis of 49.2 kDa microtubule associated protein 2c. J. Biomol. NMR. 2013;56:291–301. doi: 10.1007/s10858-013-9761-7. PubMed DOI

Nodet G., Salmon L., Ozenne V., Meier S., Jensen M.R., Blackledge M. Quantitative description of backbone conformational sampling of unfolded proteins at amino acid resolution from NMR residual dipolar couplings. J. Am. Chem. Soc. 2009;131:17908–17918. doi: 10.1021/ja9069024. PubMed DOI

Melková K., Zapletal V., Jansen S., Nomilner E., Zachrdla M., Hritz J., Nováček J., Zweckstetter M., Jensen M.R., Blackledge M., et al. Functionally specific binding regions of microtubule-associated protein 2c exhibit distinct conformations and dynamics. J. Biol. Chem. 2018;293:13297–13309. doi: 10.1074/jbc.RA118.001769. PubMed DOI PMC

Kovacech B., Skrabana R., Novak M. Transition of Tau Protein from Disordered to Misordered in Alzheimer’s Disease. Neurodegener. Dis. 2010;7:24–27. doi: 10.1159/000283478. PubMed DOI

Kontsekova E., Zilka N., Kovacech B., Skrabana R., Novak M. Identification of structural determinants on tau protein essential for its pathological function: Novel therapeutic target for tau immunotherapy in Alzheimer’s disease. Alzheimers Res. Ther. 2014;6:45. doi: 10.1186/alzrt277. PubMed DOI PMC

de Brevern A.G. Extension of the classical classification of β-turns. Sci. Rep. 2016;6:33191. doi: 10.1038/srep33191. PubMed DOI PMC

Kyte J., Doolittle R. A simple method for displaying the hydropathic character of a protein. J. Mol. Biol. 1982;157:105–132. doi: 10.1016/0022-2836(82)90515-0. PubMed DOI

Jeganathan S., von Bergen M., Brutlach H., Steinhoff H.J., Mandelkow E. Global hairpin folding of tau in solution. Biochemistry. 2006;45:2283–2293. doi: 10.1021/bi0521543. PubMed DOI

LaPointe N.E., Morfini G., Pigino G., Gaisina I.N., Kozikowski A.P., Binder L.I., Brady S.T. The amino terminus of tau inhibits kinesin-dependent axonal transport: Implications for filament toxicity. J. Neurosci. Res. 2009;87:440–451. doi: 10.1002/jnr.21850. PubMed DOI PMC

Kanaan N.M., Morfini G.A., LaPointe N.E., Pigino G.F., Patterson K.R., Song Y., Andreadis A., Fu Y., Brady S.T., Binder L.I. Pathogenic Forms of Tau Inhibit Kinesin-Dependent Axonal Transport through a Mechanism Involving Activation of Axonal Phosphotransferases. J. Neurosci. 2011;31:9858–9868. doi: 10.1523/JNEUROSCI.0560-11.2011. PubMed DOI PMC

Liao H., Li Y., Brautigan D.L., Gundersen G.G. Protein phosphatase 1 is targeted to microtubules by the microtubule- associated protein tau. J. Biol. Chem. 1998;273:21901–21908. doi: 10.1074/jbc.273.34.21901. PubMed DOI

Dente L., Vetriani C., Zucconi A., Pelicci G., Lanfrancone L., Pelicci P., Cesareni G. Modified phage peptide libraries as a tool to study specificity of phosphorylation and recognition of tyrosine containing peptides. J. Mol. Biol. 1997;269:694–703. doi: 10.1006/jmbi.1997.1073. PubMed DOI

Lee G., Thangavel R., Sharma V.M., Litersky J.M., Bhaskar K., Fang S.M., Do L.H., Andreadis A., Van Hoesen G., Ksiezak-Reding H. Phosphorylation of Tau by Fyn: Implications for Alzheimers Disease. J. Neurosci. 2004;24:2304–2312. doi: 10.1523/JNEUROSCI.4162-03.2004. PubMed DOI PMC

Stern J.L., Lessard D.V., Hoeprich G.J., Morfini G.A., Berger C.L., Drubin D.G. Phosphoregulation of Tau modulates inhibition of kinesin-1 motility. Mol. Biol. Cell. 2017;28:1079–1087. doi: 10.1091/mbc.e16-10-0728. PubMed DOI PMC

Schroer T.A. Dynactin. Annu. Rev. Cell Dev. Biol. 2004;20:759–779. doi: 10.1146/annurev.cellbio.20.012103.094623. PubMed DOI

Carter A.P., Diamant A.G., Urnavicius L. How dynein and dynactin transport cargos: A structural perspective. Curr. Opin. Struct. Biol. 2016;37:62–70. doi: 10.1016/j.sbi.2015.12.003. PubMed DOI

Magnani E., Fan J., Gasparini L., Golding M., Williams M., Schiavo G., Goedert M., Amos L.A., Spillantini M.G. Interaction of tau protein with the dynactin complex. EMBO J. 2007;26:4546–4554. doi: 10.1038/sj.emboj.7601878. PubMed DOI PMC

Brandt R., Léger J., Lee G. Interaction of tau with the neural plasma membrane mediated by taus amino-terminal projection domain. J. Cell Biol. 1995;131:1327–1340. doi: 10.1083/jcb.131.5.1327. PubMed DOI PMC

Usardi A., Pooler A.M., Seereeram A., Reynolds C.H., Derkinderen P., Anderton B., Hanger D.P., Noble W., Williamson R. Tyrosine phosphorylation of tau regulates its interactions with Fyn SH2 domains, but not SH3 domains, altering the cellular localization of tau. FEBS J. 2011;278:2927–2937. doi: 10.1111/j.1742-4658.2011.08218.x. PubMed DOI

Hernandez P., Lee G., Sjoberg M., MacCioni R.B. Tau phosphorylation by cdk5 and Fyn in response to amyloid peptide Aβ25–35: Involvement of lipid rafts. J. Alzheimers Dis. 2009;16:149–156. doi: 10.3233/JAD-2009-0933. PubMed DOI

Baulieu E.E. Neurosteroids: Of the Nervous System, By the Nervous System, For the Nervous System. Recent Progr. Horm. Res. 1997;52:1–32. PubMed

Fontaine-Lenoir V., Chambraud B., Fellous A., David S., Duchossoy Y., Baulieu E.E., Robel P. Microtubule-associated protein 2 (MAP2) is a neurosteroid receptor. Proc. Natl. Acad. Sci. USA. 2006;103:4711–4716. doi: 10.1073/pnas.0600113103. PubMed DOI PMC

Laurine E., Lafitte D., Grégoire C., Sérée E., Loret E., Douillard S., Michel B., Briand C., Verdier J.M. Specific binding of dehydroepiandrosterone to the N terminus of the microtubule-associated protein MAP2. J. Biol. Chem. 2003;278:29979–29986. doi: 10.1074/jbc.M303242200. PubMed DOI

Mizota K., Ueda H. N-terminus of MAP2C as a neurosteroid-binding site. NeuroReport. 2008;19:1529–1533. doi: 10.1097/WNR.0b013e328310fe97. PubMed DOI

Götz F., Roske Y., Schulz M.S., Autenrieth K., Bertinetti D., Faelber K., Zühlke K., Kreuchwig A., Kennedy E.J., Krause G., et al. AKAP18:PKA-RIIα structure reveals crucial anchor points for recognition of regulatory subunits of PKA. Biochem. J. 2016;473:1881–1894. doi: 10.1042/BCJ20160242. PubMed DOI PMC

Zamora-Leon S.P., Bresnick A., Backer J.M., Shafit-Zagardo B. Fyn phosphorylates human MAP-2c on tyrosine 67. J. Biol. Chem. 2005;280:1962–1970. doi: 10.1074/jbc.M411380200. PubMed DOI

Majumder P., Roy K., Singh B.K., Jana N.R., Mukhopadhyay D. Cellular levels of Grb2 and cytoskeleton stability are correlated in a neurodegenerative scenario. Dis. Models Mech. 2017;10:655–669. doi: 10.1242/dmm.027748. PubMed DOI PMC

Illenberger S., Zheng-Fischhöfer Q., Preuss U., Stamer K., Baumann K., Trinczek B., Biernat J., Godemann R., Mandelkow E.M., Mandelkow E. The endogenous and cell cycle-dependent phosphorylation of tau protein in living cells: Implications for Alzheimer’s disease. Mol. Biol. Cell. 1998;9:1495–1512. doi: 10.1091/mbc.9.6.1495. PubMed DOI PMC

Hanger D.P., Byers H.L., Wray S., Leung K.Y., Saxton M.J., Seereeram A., Reynolds C.H., Ward M.A., Anderton B.H. Novel phosphorylation sites in Tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis. J. Biol. Chem. 2007;282:23645–23654. doi: 10.1074/jbc.M703269200. PubMed DOI

Qi H., Prabakaran S., Cantrelle F.X., Chambraud B., Gunawardena J., Lippens X.G., Landrieu I. Characterization of neuronal tau protein as a target of extracellular signal-regulated kinase. J. Biol. Chem. 2016;291:7742–7753. doi: 10.1074/jbc.M115.700914. PubMed DOI PMC

Feijoo C., Campbell D.G., Jakes R., Goedert M., Cuenda A. Evidence that phosphorylation of the microtubule-associated protein Tau by SAPK4/p38δ at Thr50 promotes microtubule assembly. J. Cell Sci. 2005;118:397–408. doi: 10.1242/jcs.01655. PubMed DOI

Wray S., Saxton M., Anderton B., Hanger D. Direct analysis of tau from PSP brain identifies new phosphorylation sites and a major fragment of N-terminally cleaved tau containing four microtubule-binding repeats. J. Neurochem. 2008;105:2343–2352. doi: 10.1111/j.1471-4159.2008.05321.x. PubMed DOI

Derisbourg M., Leghay C., Chiappetta G., Fernandez-Gomez F.J., Laurent C., Demeyer D., Carrier S., Buée-Scherrer V., Blum D., Vinh J., et al. Role of the Tau N-terminal region in microtubule stabilization revealed by new endogenous truncated forms. Sci. Rep. 2015;5:9659. doi: 10.1038/srep09659. PubMed DOI PMC

Zilka N., Kovacech B., Barath P., Kontsekova E., Novák M. The self-perpetuating tau truncation circle. Biochem. Soc. Trans. 2012;40:681–686. doi: 10.1042/BST20120015. PubMed DOI

Skrabana R., Kovacech B., Filipcik P., Zilka N., Jadhav S., Smolek T., Kontsekova E., Novak M., Deli M. Neuronal Expression of Truncated Tau Efficiently Promotes Neurodegeneration in Animal Models: Pitfalls of Toxic Oligomer Analysis. J. Alzheimers Dis. 2017;58:1017–1025. doi: 10.3233/JAD-161124. PubMed DOI

Berling B., Wille H., Roll B., Mandelkow E.M., Garner C., Mandelkow E. Phosphorylation of microtubule-associated proteins MAP2a,b and MAP2c at Ser136 by proline-directed kinases in vivo and in vitro. Eur. J. Cell Biol. 1994;64:120–130. PubMed

Philpot B.D., Lim J.H., Halpain S., Brunjes P.C. Experience-Dependent Modifications in MAP2 Phosphorylation in Rat Olfactory Bulb. J. Neurosci. 1997;17:9596–9604. doi: 10.1523/JNEUROSCI.17-24-09596.1997. PubMed DOI PMC

Woolf N., Zinnerman M., Johnson G. Hippocampal microtubule-associated protein-2 alterations with contextual memory. Brain Res. 1999;821:241–249. doi: 10.1016/S0006-8993(99)01064-1. PubMed DOI

Tie L., Zhang J.Z., Lin Y.H., Su T.H., Li Y.H., Wu H.L., Zhang Y.Y., Yu H.M., Li X.J. Epinephrine increases phosphorylation of MAP-2c in rat pheochromocytoma cells (PC12 Cells) via a protein kinase C- and mitogen activated protein kinase-dependent mechanism. J. Proteome. Res. 2008;7:1704–1711. doi: 10.1021/pr700711s. PubMed DOI

Alexa A., Schmidt G., Tompa P., Ogueta S., Vázquez J., Kulcsár P., Kovács J., Dombrádi V., Friedrich P. The phosphorylation state of threonine-220, a uniquely phosphatase-sensitive protein kinase A site in microtubule-associated protein MAP2c, regulates microtubule binding and stability. Biochemistry. 1992;41:12427–12435. doi: 10.1021/bi025916s. PubMed DOI

Joo Y., Schumacher B., Landrieu I., Bartel M., Smet-Nocca C., Jang A., Choi H.S., Jeon N.L., Chang K.A., Kim H.S., et al. Involvement of 14-3-3 in tubulin instability and impaired axon development is mediated by Tau. FASEB J. 2015;29:4133–4144. doi: 10.1096/fj.14-265009. PubMed DOI

Valencia R., Walko G., Janda L., Novaček J., Mihailovska E., Reipert S., Andrä-Marobela K., Wiche G. Intermediate filament-associated cytolinker plectin 1c destabilizes microtubules in keratinocytes. Mol. Biol. Cell. 2013;24:768–784. doi: 10.1091/mbc.e12-06-0488. PubMed DOI PMC

He H.J., Wang X.S., Pan R., Wang D.L., Liu M.N., He R.Q. The proline-rich domain of tau plays a role in interactions with actin. BMC Cell Biol. 2009;10:81. doi: 10.1186/1471-2121-10-81. PubMed DOI PMC

Gohar M., Yang W., Strong W., Volkening K., Leystra-Lantz C., Strong M.J. Tau phosphorylation at threonine-175 leads to fibril formation and enhanced cell death: Implications for amyotrophic lateral sclerosis with cognitive impairment. J. Neurochem. 2009;108:634–643. doi: 10.1111/j.1471-4159.2008.05791.x. PubMed DOI

Moszczynski A.J., Strong W., Xu K., McKee A., Brown A., Strong M.J. Pathologic Thr175 tau phosphorylation in CTE and CTE with ALS. Neurology. 2018;90:e380–e387. doi: 10.1212/WNL.0000000000004899. PubMed DOI PMC

Moszczynski A.J., Gohar M., Volkening K., Leystra-Lantz C., Strong W., Strong M.J. Thr175-phosphorylated tau induces pathologic fibril formation via GSK3β-mediated phosphorylation of Thr231 in vitro. Neurobiol. Aging. 2015;36:1590–1599. doi: 10.1016/j.neurobiolaging.2014.12.001. PubMed DOI

Gandhi N.S., Landrieu I., Byrne C., Kucic P., Cantrelle F.X., Wieruszeski J.M., L M.R., Jacquot Y., Lippens G. A Phosphorylation-Induced Turn Defines the Alzheimer’s Disease AT8 Antibody Epitope on the Tau Protein. Angew. Chem. Int. Ed. 2015;54:6819–6823. doi: 10.1002/anie.201501898. PubMed DOI

Ittner A., Chua S.W., Bertz J., Volkerling A., van der Hoven J., Gladbach A., Przybyla M., Bi M., van Hummel A., Stevens C.H., et al. Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer’s mice. Science. 2016;354:904–908. doi: 10.1126/science.aah6205. PubMed DOI

Despres C., Byrne C., Qi H., Cantrelle F.X., Huvent I., Chambraud B., Baulieu E.E., Jacquot Y., Landrieu I., Lippens G., et al. Identification of the Tau phosphorylation pattern that drives its aggregation. Proc. Natl. Acad. Sci. USA. 2017;114:9080–9085. doi: 10.1073/pnas.1708448114. PubMed DOI PMC

Malia T.J., Teplyakov A., Ernst R., Wu S.J., Lacy E.R., Liu X., Vandermeeren M., Mercken M., Luo J., Sweet R.W., et al. Epitope mapping and structural basis for the recognition of phosphorylated tau by the anti-tau antibody AT8. Proteins Struct. Funct. Bioinf. 2016;84:427–434. doi: 10.1002/prot.24988. PubMed DOI PMC

Hashiguchi M., Hashiguchi T. Chapter Four—Kinase-Kinase Interaction and Modulation of Tau Phosphorylation. In: Jeon K.W., editor. International Review of Cell and Molecular Biology. Volume 300. Academic Press; Cambridge, MA, USA: 2013. pp. 121–160. PubMed

Yang P.H., Zhu J.X., Huang Y.D., Zhang X.Y., Lei P., Bush A., Xiang Q., Su Z., Zhang Q.H. Human Basic Fibroblast Growth Factor Inhibits Tau Phosphorylation via the PI3K/Akt-GSK3β Signaling Pathway in a 6-Hydroxydopamine-Induced Model of Parkinson’s Disease. Neurodegener. Dis. 2016;16:357–369. doi: 10.1159/000445871. PubMed DOI

Amniai L., Barbier P., Sillen A., Wieruszeski J.M., Peyrot V., Lippens G., Landrieu I. Alzheimer disease specific phosphoepitopes of Tau interfere with assembly of tubulin but not binding to microtubules. FASEB J. 2009;23:1146–1152. doi: 10.1096/fj.08-121590. PubMed DOI

Komulainen E., Zdrojewska J., Freemantle E., Mohammad H., Kulesskaya N., Deshpande P., Marchisella F., Mysore R., Hollos P., Michelsen K.A., et al. JNK1 controls dendritic field size in L2/3 and L5 of the motor cortex, constrains soma size, and influences fine motor coordination. Front. Cell. Neurosci. 2014;8:272. doi: 10.3389/fncel.2014.00272. PubMed DOI PMC

Reynolds C.H., Garwood C.J., Wray S., Price C., Kellie S., Perera T., Zvelebil M., Yang A., Sheppard P.W., Varndell I.M., et al. Phosphorylation regulates tau interactions with Src homology 3 domains of phosphatidylinositol 3-kinase, phospholipase Cγ1, Grb2, and Src family kinases. J. Biol. Chem. 2008;283:18177–18186. doi: 10.1074/jbc.M709715200. PubMed DOI

Yoshida H., Goedert M. Sequential phosphorylation of tau protein by cAMP-dependent protein kinase and SAPK4/p38delta or JNK2 in the presence of heparin generates the AT100 epitope. J. Neurochem. 2006;99:154–164. doi: 10.1111/j.1471-4159.2006.04052.x. PubMed DOI

Landrieu I., Lacosse L., Leroy A., Wieruszeski J.M., Trivelli X., Sillen A., Sibille N., Schwalbe H., Saxena K., Langer T., et al. NMR analysis of a Tau phosphorylation pattern. J. Am. Chem. Soc. 2006;128:3575–3583. doi: 10.1021/ja054656+. PubMed DOI

Sadik G., Tanaka T., Kato K., Yamamori H., Nessa B.N., Morihara T., Takeda M. Phosphorylation of tau at Ser214 mediates its interaction with 14-3-3 protein: Implications for the mechanism of tau aggregation. J. Neurochem. 2009;108:33–43. doi: 10.1111/j.1471-4159.2008.05716.x. PubMed DOI

Sluchanko N.N., Seit-Nebi A.S., Gusev N.B. Effect of phosphorylation on interaction of human tau protein with 14-3-3zeta. Biochem. Biophys. Res. Commun. 2009;379:990–994. doi: 10.1016/j.bbrc.2008.12.164. PubMed DOI

Sluchanko N.N., Seit-Nebi A.S., Gusev N.B. Phosphorylation of more than one site is required for tight interaction of human tau protein with 14-3-3zeta. FEBS Lett. 2009;583:2739–4272. doi: 10.1016/j.febslet.2009.07.043. PubMed DOI

Sluchanko N.N., Gusev N.B. 14-3-3 proteins and regulation of cytoskeleton. Biochemistry. 2010;75:1528–1546. doi: 10.1134/S0006297910130031. PubMed DOI

Johnson C., Crowther S., Stafford M., Campbell D., Toth R., MacKintosh C. Bioinformatic and experimental survey of 14-3-3-binding sites. Biochem. J. 2010;427:69–78. doi: 10.1042/BJ20091834. PubMed DOI PMC

Zamora-Leon S.P., Lee G., Davies P., Shafit-Zagardo B. Binding of Fyn to MAP-2c through an SH3 binding domain. J. Biol. Chem. 2001;276:39950–39958. doi: 10.1074/jbc.M107807200. PubMed DOI

Andrei S.A., Meijer F.A., Neves J.F., Brunsveld L., Landrieu I., Ottmann C., Milroy L.G. Inhibition of 14-3-3/Tau by Hybrid Small-Molecule Peptides Operating via Two Different Binding Modes. ACS Chem. Neurocsi. 2018;9:2639–2654. doi: 10.1021/acschemneuro.8b00118. PubMed DOI PMC

Gigant B., Landrieu I., Fauquan C., Barbie P., Huvent I., Wieruszeski J.M., Knossow M., Lippens G. Mechanism of Tau-Promoted Microtubule Assembly As Probed by NMR Spectroscopy. J. Am. Chem. Soc. 2014;136:12615–12623. doi: 10.1021/ja504864m. PubMed DOI

von Bergen M., Friedhoff P., Biernat J., Heberle J., Mandelkow E.M., Mandelkow E. Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif ((306)VQIVYK(311)) forming beta structure. Proc. Natl. Acad. Sci. USA. 2000;97:5129–5134. doi: 10.1073/pnas.97.10.5129. PubMed DOI PMC

Wang R.Y.R., Song Y., Barad B.A., Cheng Y., Fraser J.S., DiMaio F. Automated structure refinement of macromolecular assemblies from cryo-EM maps using Rosetta. eLife. 2016;5:e17219. doi: 10.7554/eLife.17219. PubMed DOI PMC

Al-Bassam J., Ozer R.S., Safer D., Halpain S., Milligan R.A. MAP2 and tau bind longitudinally along the outer ridges of microtubule protofilaments. J. Cell Biol. 2002;157:1187–1196. doi: 10.1083/jcb.200201048. PubMed DOI PMC

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. 2003;22:70–77. doi: 10.1093/emboj/cdg001. PubMed DOI PMC

Drewes G., Trinczek B., Illenberger S., Biernat J., Schmitt-Ulms G., Meyer H.E., Mandelkow E.M., Mandelkow E. Microtubule-associated Protein/Microtubule Affinity-regulating Kinase (p110mark): A novel protein kinase that regulates tau-microtubule interactions and dynamic instability by phosphorylation at the Alzheimer-specific site serine 262. J. Biol. Chem. 1995;270:7679–7688. doi: 10.1074/jbc.270.13.7679. PubMed DOI

Illenberger S., Drewes G., Trinczek B., Biernat J., Meyer H.E., Olmsted J.B., Mandelkow E.M., Mandelkow E. Phosphorylation of microtubule-associated proteins MAP2 and MAP4 by the protein kinase p110mark. Phosphorylation sites and regulation of microtubule dynamics. J. Biol. Chem. 1996;271:10834–10843. doi: 10.1074/jbc.271.18.10834. PubMed DOI

Brandt R., Lee G., Teplow D.B., Shalloway D., Abdel-Ghany M. Differential Effect of Phosphorylation and Substrate Modulation on Tau’s Ability to Promote Microtubule Growth and Nucleation. J. Biol. Chem. 1994;269:11776–11782. PubMed

Itoh T.J., Hisanaga S., Hosoi T., Kishimoto T., Hotani H. Phosphorylation states of microtubule-associated protein 2 (MAP2) determine the regulatory role of MAP2 in microtubule dynamics. Biochemistry. 1997;36:12574–12582. doi: 10.1021/bi962606z. PubMed DOI

Schneider A., Biernat J., von Bergen M., Mandelkow E., Mandelkow E.M. Phosphorylation that Detaches Tau Protein from Microtubules (Ser262, Ser214) Also Protects It against Aggregation into Alzheimer Paired Helical Filaments. Biochemistry. 1999;38:3549–3558. doi: 10.1021/bi981874p. PubMed DOI

Sattilaro R.F. Interaction of microtubule-associated protein 2 with actin filaments. Biochemistry. 1986;25:2003–2009. doi: 10.1021/bi00356a025. PubMed DOI

Ozer R.S., Halpain S. Phosphorylation-dependent localization of microtubule-associated protein MAP2c to the actin cytoskeleton. Mol. Biol. Cell. 2000;11:3573–3587. doi: 10.1091/mbc.11.10.3573. PubMed DOI PMC

Al-Hilaly Y.K., Pollack S.J., Vadukul D.M., Citossi F., Rickard J.E., Simpson M., Storey J.M., Harrington C.R., Wischik C.M., Serpell L.C. Alzheimer’s Disease-like Paired Helical Filament Assembly from Truncated Tau Protein Is Independent of Disulfide Crosslinking. J. Mol. Biol. 2017;429:3650–3665. doi: 10.1016/j.jmb.2017.09.007. PubMed DOI

Xie C., Miyasaka T., Yoshimura S., Hatsuta H., Yoshina S., Kage-Nakadai E., Mitani S., Murayama S., Ihara Y. The homologous carboxyl-terminal domains of microtubule-associated protein 2 and TAU induce neuronal dysfunction and have differential fates in the evolution of neurofibrillary tangles. PLoS ONE. 2014;9:e89796. doi: 10.1371/journal.pone.0089796. PubMed DOI PMC

Gómez-Ramos A., Díaz-Hernández M., Rubio A., Miras-Portugal M.T., Avila J. Extracellular tau promotes intracellular calcium increase through M1 and M3 muscarinic receptors in neuronal cells. Mol. Cell. Neurosci. 2008;37:673–681. doi: 10.1016/j.mcn.2007.12.010. PubMed DOI

Li T., Paudel H.K. Glycogen Synthase Kinase 3β Phosphorylates Alzheimer’s Disease-Specific Ser396 of Microtubule-Associated Protein Tau by a Sequential Mechanism. Biochemistry. 2006;45:3125–3133. doi: 10.1021/bi051634r. PubMed DOI

Díaz-Hernández M., Gómez-Ramos A., Rubio A., Gómez-Villafuertes R., Naranjo J.R., Teresa Miras-Portugal M., Avila J. Tissue-nonspecific alkaline phosphatase promotes the neurotoxicity effect of extracellular tau. J. Biol. Chem. 2010;285:32539–35248. doi: 10.1074/jbc.M110.145003. PubMed DOI PMC

Berry R.W., Abraha A., Lagalwar S., LaPointe N., Gamblin T.C., Cryns V.L., Binder L.I. Inhibition of Tau Polymerization by Its Carboxy-Terminal Caspase Cleavage Fragment. Biochemistry. 2003;42:8325–8331. doi: 10.1021/bi027348m. PubMed DOI

Fifre A., Sponne I., Koziel V., Kriem B., Potin F.T.Y., Bihain B.E., Olivier J.L., Oster T., Pillot T. Microtubule-associated Protein MAP1A, MAP1B, and MAP2 Proteolysis during Soluble Amyloid β-Peptide-induced Neuronal Apoptosis: Synergistic Involvement of Calpain and Caspase-3. J. Biol. Chem. 2006;281:229–240. doi: 10.1074/jbc.M507378200. PubMed DOI

Walker S., Ullman O., Stultz C.M. Using intramolecular disulfide bonds in tau protein to deduce structural features of aggregation-resistant conformations. J. Biol. Chem. 2012;287:9591–9600. doi: 10.1074/jbc.M111.336107. PubMed DOI PMC

Crowe A., James M.J., Virginia M.Y., Smith A.B., Trojanowski J.Q., Ballatore C., Brunden K.R. Aminothienopyridazines and methylene blue affect Tau fibrillization via cysteine oxidation. J. Biol. Chem. 2013;288:11024–11037. doi: 10.1074/jbc.M112.436006. PubMed DOI PMC

De Ancos J.G., Correas I., Avila J. Differences in microtubule binding and self-association abilities of bovine brain tau isoforms. J. Biol. Chem. 1993;268:7976–7982. PubMed

Paudel H.K. Phosphorylation by neuronal cdc2-like protein kinase promotes dimerization of tau protein in vitro. J. Biol. Chem. 1997;272:28328–28334. doi: 10.1074/jbc.272.45.28328. PubMed DOI

Wille H., Mandelkow E.M., Mandelkow E. The Juvenile Microtubule-associated Protein MAP2c Is a Rod-like Molecule That Forms Antiparallel Dimer. J. Biol. Chem. 1992;267:10737–10742. PubMed

Goode B.L., Denis P.E., Panda D., Radeke M.J., Miller H.P., Wilson L., Feinstein S.C. Functional interactions between the proline-rich and repeat regions of tau enhance microtubule binding and assembly. Mol. Biol. Cell. 1997;8:353–365. doi: 10.1091/mbc.8.2.353. PubMed DOI PMC

Guo Y., Gong H.S., Zhang J., Xie W.L., Tian C., Chen C., Shi Q., Wang S.B., Xu Y., Zhang B.Y., et al. Remarkable reduction of MAP2 in the brains of scrapie-infected rodents and human prion disease possibly correlated with the increase of calpain. PLoS ONE. 2012;7:e30163. doi: 10.1371/journal.pone.0030163. PubMed DOI PMC

Ackmann M., Wiech H., Mandelkow E. Nonsaturable binding indicates clustering of tau on the microtubule surface in a paired helical filament-like conformation. J. Biol. Chem. 2000;275:30335–30343. doi: 10.1074/jbc.M002590200. PubMed DOI

Meixner A., Haverkamp S., Wässle H., Führer S., Thalhammer J., Kropf N., Bittner R.E., Lassmann H., Wiche G., Propst F. MAP1B is required for axon guidance and Is involved in the development of the central and peripheral nervous system. J. Cell Biol. 2000;151:1169–1178. doi: 10.1083/jcb.151.6.1169. PubMed DOI PMC

Liu F., Iqbal K., Grundke-Iqbal I., Rossie S., Gong C.X. Dephosphorylation of tau by protein phosphatase 5: Impairment in Alzheimer’s disease. J. Biol. Chem. 2005;280:1790–1796. doi: 10.1074/jbc.M410775200. PubMed DOI

Tompa P., Schad E., Tantos A., Kalmar L. Intrinsically disordered proteins: Emerging interaction specialists. Curr. Opin. Struct. Biol. 2015;35:49–59. doi: 10.1016/j.sbi.2015.08.009. PubMed DOI

Specific phosphorylation of microtubule-associated protein 2c by extracellular signal-regulated kinase reduces interactions at its Pro-rich regions

NMR Studies of Tau Protein in Tauopathies

Proteomic Analysis Unveils Expressional Changes in Cytoskeleton- and Synaptic Plasticity-Associated Proteins in Rat Brain Six Months after Withdrawal from Morphine

Choice of Force Field for Proteins Containing Structured and Intrinsically Disordered Regions