Structural insight into microtubule stabilization and kinesin inhibition by Tau family MAPs
Open accessAbstract
The Tau family microtubule-associated proteins (MAPs) promote microtubule stabilization and regulate microtubule-based motility. They share the C-terminal microtubule-binding domain, which includes three to five tubulin-binding repeats. Different numbers of repeats formed by alternative splicing have distinct effects on the activities of these proteins, and the distribution of these variants regulates fundamental physiological phenomena in cells. In this study, using cryo-EM, we visualized the MAP4 microtubule complex with the molecular motor kinesin-1. MAP4 bound to the C-terminal domains of tubulins along the protofilaments stabilizes the longitudinal contacts of the microtubule. The strongest bond of MAP4 was found around the intertubulin–dimer interface such that MAP4 coexists on the microtubule with kinesin-1 bound to the intratubulin–dimer interface as well. MAP4, consisting of five repeats, further folds and accumulates above the intertubulin–dimer interface, interfering with kinesin-1 movement. Therefore, these cryo-EM studies reveal new insight into the structural basis of microtubule stabilization and inhibition of kinesin motility by the Tau family MAPs.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
MAP4 adopts a conformation completely distinct from that of tau on microtubules, which may at least partially explain why MAP4 is unable to form envelopes.
“MAP4 adopts a conformation completely distinct from that of tau41,44 on microtubules, which may at least partially explain why, unlike tau, MAP4 is unable to form envelopes.”
From Microtubule lattice spacing governs cohesive envelope formation of tau family proteins (2022) · cites this paper as [44]
The Results section (“Structural detail of MAP4–kinesin-1–microtubule binding”; page unavailable) suggests that 5R-MAP4 cannot adopt a Tau-like elongated structure in the presence of kinesin-1. It does not establish that MAP4’s conformation is completely distinct from Tau’s under all conditions, or address whether MAP4 can form envelopes. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMAP4 did not block the binding of a kinesin-1 motor domain to microtubules in prior experiments, while the present study shows it negatively affects KIF1A motility.
“In prior experiments, MAP4 did not block the binding of a kinesin-1 motor domain to microtubules44, while we show that it negatively affects KIF1A motility.”
From Microtubule lattice spacing governs cohesive envelope formation of tau family proteins (2022) · cites this paper as [44]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Cryo-EM structures of tau filaments from Alzheimer’s disease
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. (2017) · Nature · doi:10.1038/nature23002 · Cited by 2,061 · cited 1× · see citing works
“Tau is known to form filamentous aggregates called neurofibrillary tangles whose structure were recently reported by high-resolution cryo-EM study without microtubules (Fitzpatrick et al., 2017).”
BackgroundDifferential Regulation of Dynein and Kinesin Motor Proteins by Tau
Dixit, R., Ross, J. L., Goldman, Y. E., & Holzbaur, E. L. F. (2008) · Science · doi:10.1126/science.1152993 · Cited by 1,012 · see citing works
MAP2 and tau bind longitudinally along the outer ridges of microtubule protofilaments
Al-Bassam, J., Ozer, R. S., Safer, D., Halpain, S., & Milligan, R. A. (2002) · The Journal of Cell Biology · doi:10.1083/jcb.200201048 · Cited by 327 · see citing works
Single-molecule investigation of the interference between kinesin, tau and MAP2c
Seitz, A., Kojima, H., Oiwa, K., Mandelkow, E.-M., Song, Y.-H., & Mandelkow, E. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf503 · Cited by 257 · see citing works
Flagged first, then by citations
Research works printed but not linked: 41
- Aizawa H., Emori Y., Murofushi H., Kawasaki H., Sakai H., and Suzuki K. 1990 Molecular cloning of a ubiquitously distributed microtubule-associated protein with Mr 190,000. J. Biol. Chem. 265: 13849– 13855. 2380192
- Atherton J., Farabella I., Yu I.M., Rosenfeld S.S., Houdusse A., Topf M., and Moores C.A. 2014 Conserved mechanisms of microtubule-stimulated ADP release, ATP binding, and force generation in transport kinesins. eLife. 3: e03680 10.7554/eLife.03680 25209998 PMC4358365 · DOI
- Chau M.F., Radeke M.J., de Inés C., Barasoain I., Kohlstaedt L.A., and Feinstein S.C. 1998 The microtubule-associated protein tau cross-links to two distinct sites on each alpha and beta tubulin monomer via separate domains. Biochemistry. 37: 17692– 17703. 10.1021/bi9812118 9922135 · DOI
- Chen J., Kanai Y., Cowan N.J., and Hirokawa N. 1992 Projection domains of MAP2 and tau determine spacings between microtubules in dendrites and axons. Nature. 360: 674– 677. 10.1038/360674a0 1465130 · DOI · Paper page
- Cheng G., Qiao F., Gallien T.N., Kuppuswamy D., and Cooper G. IV 2005 Inhibition of beta-adrenergic receptor trafficking in adult cardiocytes by MAP4 decoration of microtubules. Am. J. Physiol. Heart Circ. Physiol. 288: H1193– H1202. 10.1152/ajpheart.00109.2004 15528234 · DOI
- Dehmelt L., and Halpain S. 2005 The MAP2/Tau family of microtubule-associated proteins. Genome Biol. 6: 204 10.1186/gb-2004-6-1-204 15642108 PMC549057 · DOI · Paper page
- Drewes G., Ebneth A., and Mandelkow E.M. 1998 MAPs, MARKs and microtubule dynamics. Trends Biochem. Sci. 23: 307– 311. 10.1016/S0968-0004(98)01245-6 9757832 · DOI
- Ebneth A., Godemann R., Stamer K., Illenberger S., Trinczek B., and Mandelkow E. 1998 Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer’s disease. J. Cell Biol. 143: 777– 794. 10.1083/jcb.143.3.777 9813097 PMC2148132 · DOI · Paper page
- Ennulat D.J., Liem R.K., Hashim G.A., and Shelanski M.L. 1989 Two separate 18-amino acid domains of tau promote the polymerization of tubulin. J. Biol. Chem. 264: 5327– 5330. 2494161
- Fishilevich S., Zimmerman S., Kohn A., Iny Stein T., Olender T., Kolker E., Safran M., and Lancet D. 2016 Genic insights from integrated human proteomics in GeneCards. Database (Oxford). 2016: baw030 10.1093/database/baw030 27048349 PMC4820835 · DOI
- Gamblin T.C., Nachmanoff K., Halpain S., and Williams R.C. Jr 1996 Recombinant microtubule-associated protein 2c reduces the dynamic instability of individual microtubules. Biochemistry. 35: 12576– 12586. 10.1021/bi961135d 8823195 · DOI
- Gard D.L., and Kirschner M.W. 1987 Microtubule assembly in cytoplasmic extracts of Xenopus oocytes and eggs. J. Cell Biol. 105: 2191– 2201. 10.1083/jcb.105.5.2191 3680377 PMC2114874 · DOI
- Grigorieff N. 2007 FREALIGN: high-resolution refinement of single particle structures. J. Struct. Biol. 157: 117– 125. 10.1016/j.jsb.2006.05.004 16828314 · DOI
- Hagiwara H., Yorifuji H., Sato-Yoshitake R., and Hirokawa N. 1994 Competition between motor molecules (kinesin and cytoplasmic dynein) and fibrous microtubule-associated proteins in binding to microtubules. J. Biol. Chem. 269: 3581– 3589. 8106402
- Hardy J., Duff K., Hardy K.G., Perez-Tur J., and Hutton M. 1998 Genetic dissection of Alzheimer’s disease and related dementias: amyloid and its relationship to tau. Nat. Neurosci. 1: 355– 358. 10.1038/1565 10196523 · DOI
- Hirokawa N., Shiomura Y., and Okabe S. 1988 Tau proteins: the molecular structure and mode of binding on microtubules. J. Cell Biol. 107: 1449– 1459. 10.1083/jcb.107.4.1449 3139677 PMC2115262 · DOI
- Joly J.C., Flynn G., and Purich D.L. 1989 The microtubule-binding fragment of microtubule-associated protein-2: location of the protease-accessible site and identification of an assembly-promoting peptide. J. Cell Biol. 109: 2289– 2294. 10.1083/jcb.109.5.2289 2808529 PMC2115882 · DOI
- Kar S., Fan J., Smith M.J., Goedert M., and Amos L.A. 2003 Repeat motifs of tau bind to the insides of microtubules in the absence of taxol. EMBO J. 22: 70– 77. 10.1093/emboj/cdg001 12505985 PMC140040 · DOI · Paper page
- Kellogg E.H., Hejab N.M.A., Poepsel S., Downing K.H., DiMaio F., and Nogales E. 2018 Near-atomic model of microtubule-tau interactions. Science. 360: 1242– 1246. 10.1126/science.aat1780 29748322 PMC6225777 · DOI · Paper page
- Kremer J.R., Mastronarde D.N., and McIntosh J.R. 1996 Computer visualization of three-dimensional image data using IMOD. J. Struct. Biol. 116: 71– 76. 10.1006/jsbi.1996.0013 8742726 · DOI
- Kucukelbir A., Sigworth F.J., and Tagare H.D. 2014 Quantifying the local resolution of cryo-EM density maps. Nat. Methods. 11: 63– 65. 10.1038/nmeth.2727 24213166 PMC3903095 · DOI
- Li X., Mooney P., Zheng S., Booth C.R., Braunfeld M.B., Gubbens S., Agard D.A., and Cheng Y. 2013 Electron counting and beam-induced motion correction enable near-atomic-resolution single-particle cryo-EM. Nat. Methods. 10: 584– 590. 10.1038/nmeth.2472 23644547 PMC3684049 · DOI
- Mastronarde D.N. 2005 Automated electron microscope tomography using robust prediction of specimen movements. J. Struct. Biol. 152: 36– 51. 10.1016/j.jsb.2005.07.007 16182563 · DOI
- Metlagel Z., Kikkawa Y.S., and Kikkawa M. 2007 Ruby-Helix: an implementation of helical image processing based on object-oriented scripting language. J. Struct. Biol. 157: 95– 105. 10.1016/j.jsb.2006.07.015 16996276 · DOI
- Mindell J.A., and Grigorieff N. 2003 Accurate determination of local defocus and specimen tilt in electron microscopy. J. Struct. Biol. 142: 334– 347. 10.1016/S1047-8477(03)00069-8 12781660 · DOI
- Mogessie B., Roth D., Rahil Z., and Straube A. 2015 A novel isoform of MAP4 organises the paraxial microtubule array required for muscle cell differentiation. eLife. 4: e05697 10.7554/eLife.05697 25898002 PMC4423121 · DOI
- Morikawa M., Yajima H., Nitta R., Inoue S., Ogura T., Sato C., and Hirokawa N. 2015 X-ray and Cryo-EM structures reveal mutual conformational changes of Kinesin and GTP-state microtubules upon binding. EMBO J. 34: 1270– 1286. 10.15252/embj.201490588 25777528 PMC4426485 · DOI
- Mozziconacci J., Sandblad L., Wachsmuth M., Brunner D., and Karsenti E. 2008 Tubulin dimers oligomerize before their incorporation into microtubules. PLoS One. 3: e3821 10.1371/journal.pone.0003821 19043587 PMC2584370 · DOI
- Panda D., Samuel J.C., Massie M., Feinstein S.C., and Wilson L. 2003 Differential regulation of microtubule dynamics by three- and four-repeat tau: implications for the onset of neurodegenerative disease. Proc. Natl. Acad. Sci. USA. 100: 9548– 9553. 10.1073/pnas.1633508100 12886013 PMC170955 · DOI · Paper page
- Pettersen E.F., Goddard T.D., Huang C.C., Couch G.S., Greenblatt D.M., Meng E.C., and Ferrin T.E. 2004 UCSF Chimera—a visualization system for exploratory research and analysis. J. Comput. Chem. 25: 1605– 1612. 10.1002/jcc.20084 15264254 · DOI
- Santarella R.A., Skiniotis G., Goldie K.N., Tittmann P., Gross H., Mandelkow E.M., Mandelkow E., and Hoenger A. 2004 Surface-decoration of microtubules by human tau. J. Mol. Biol. 339: 539– 553. 10.1016/j.jmb.2004.04.008 15147841 · DOI
- Scheres S.H. 2012 RELION: implementation of a Bayesian approach to cryo-EM structure determination. J. Struct. Biol. 180: 519– 530. 10.1016/j.jsb.2012.09.006 23000701 PMC3690530 · DOI · Paper page
- Schweers O., Schönbrunn-Hanebeck E., Marx A., and Mandelkow E. 1994 Structural studies of tau protein and Alzheimer paired helical filaments show no evidence for beta-structure. J. Biol. Chem. 269: 24290– 24297. 7929085
- Spillantini M.G., and Goedert M. 1998 Tau protein pathology in neurodegenerative diseases. Trends Neurosci. 21: 428– 433. 10.1016/S0166-2236(98)01337-X 9786340 · DOI · Paper page
- Tokuraku K., Matsushima K., Matui T., Nakagawa H., Katsuki M., Majima R., and Kotani S. 2003 The number of repeat sequences in microtubule-associated protein 4 affects the microtubule surface properties. J. Biol. Chem. 278: 29609– 29618. 10.1074/jbc.M302186200 12773533 · DOI
- Tokuraku K., Noguchi T.Q., Nishie M., Matsushima K., and Kotani S. 2007 An isoform of microtubule-associated protein 4 inhibits kinesin-driven microtubule gliding. J. Biochem. 141: 585– 591. 10.1093/jb/mvm063 17317690 · DOI
- Trinczek B., Ebneth A., Mandelkow E.M., and Mandelkow E. 1999 Tau regulates the attachment/detachment but not the speed of motors in microtubule-dependent transport of single vesicles and organelles. J. Cell Sci. 112: 2355– 2367. 10381391
- Yajima H., Ogura T., Nitta R., Okada Y., Sato C., and Hirokawa N. 2012 Conformational changes in tubulin in GMPCPP and GDP-taxol microtubules observed by cryoelectron microscopy. J. Cell Biol. 198: 315– 322. 10.1083/jcb.201201161 22851320 PMC3413364 · DOI
- Yamagishi M., Shigematsu H., Yokoyama T., Kikkawa M., Sugawa M., Aoki M., Shirouzu M., Yajima J., and Nitta R. 2016 Structural Basis of Backwards Motion in Kinesin-1-Kinesin-14 Chimera: Implication for Kinesin-14 Motility. Structure. 24: 1322– 1334. 10.1016/j.str.2016.05.021 27452403 · DOI
- Zhang R., and Nogales E. 2015 A new protocol to accurately determine microtubule lattice seam location. J. Struct. Biol. 192: 245– 254. 10.1016/j.jsb.2015.09.015 26424086 PMC4634897 · DOI
- Zhang C., Chen B., Guo A., Zhu Y., Miller J.D., Gao S., Yuan C., Kutschke W., Zimmerman K., Weiss R.M., 2014 Microtubule-mediated defects in junctophilin-2 trafficking contribute to myocyte transverse-tubule remodeling and Ca2+ handling dysfunction in heart failure. Circulation. 129: 1742– 1750. 10.1161/CIRCULATIONAHA.113.008452 24519927 PMC4006305 · DOI
Cited by
Sorted by citations
A combinatorial MAP code dictates polarized microtubule transport
Monroy, B. Y., Tan, T. C., Oclaman, J. M., Han, J. S., Simó, S., Niwa, S., Nowakowski, D. W., McKenney, R. J., & Ori-McKenney, K. M. (2020) · Developmental Cell · doi:10.1016/j.devcel.2020.01.029 · Cited by 157 · see citing works
Microtubule lattice spacing governs cohesive envelope formation of tau family proteins
Siahaan, V., Tan, R., Humhalova, T., Libusova, L., Lacey, S. E., Tan, T., Dacy, M., Ori-McKenney, K. M., McKenney, R. J., Braun, M., et al. (2022) · Nature Chemical Biology · doi:10.1038/s41589-022-01096-2 · Cited by 94 · see citing works
- Authors
- Shigematsu, H., Imasaki, T., Doki, C., Sumi, T., Aoki, M., Uchikubo-Kamo, T., Sakamoto, A., Tokuraku, K., Shirouzu, M., & Nitta, R.
- Affiliations
- SPring-8 (JP)
- Japan Science and Technology Agency (JP)
- Muroran Institute of Technology (JP)
- Kobe University (JP)
- RIKEN (JP)
- RIKEN Center for Life Science Technologies, Yokohama, Japan 1
- Corresponding author
- Nitta, Ryo
- ORCID
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2018-10-01
- Volume
- 217
- Issue
- 12
- Pages
- 4155-4163
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC6279373
- OpenAlex
- W2895627537
- Cited by
- 54
- References
- 4
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 5 · 2023: 8 · 2022: 5 · 2021: 8 · 2020: 9 · 2019: 5
- FWCI
- 3.01
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (acceptedVersion)
- Kobe University Repository Kernel (Kobe University) (submittedVersion, cc-by-nc-sa)
- Funders
- Japan Society for the Promotion of Science (16K14704, 15H01656, 17H05897, 15K08168)
- Japan Agency for Medical Research and Development (1005341)
- Japan Science and Technology Agency
- PRESTO (JPMJPR14L2)
- Takeda Science Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Uehara Memorial Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Oncology › Cancer Treatment and Pharmacology
- Keywords
- MAP4, kinesin-1, microtubule stabilization, alternative splicing, microtubule protofilaments, cryo-EM structure, microtubule motility
- MeSH terms
- Humans, Microtubule-Associated Proteins, Microtubules, Kinesins
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
