Skip to main content
SpringerLink
Log in

Overview of the mechanism of cytoskeletal motors based on structure

  • Review
  • Published:
Biophysical Reviews Aims and scope Submit manuscript

Abstract

In the last two decades, a wealth of structural and functional knowledge has been obtained for the three major cytoskeletal motor proteins, myosin, kinesin and dynein, which we review here. The cytoskeletal motor proteins myosin and kinesin are structurally similar in the core architecture of their motor domains and have similar force-producing mechanisms that are coupled with the chemical cycles of ATP binding, hydrolysis, Pi release and subsequent ADP release. The force is generated through conformational changes in the motor domain during Pi release and ATP binding in myosin and kinesin, respectively, and then converted into the rotation of the lever arm or neck linker (referred to as a power stroke) through the common structural pathways. On the other hand, the dynein cytoskeletal motor is an AAA+ protein and has a different structure and power stroke mechanism from those of myosins and kinesins. The linker protruding from the AAA+ ring of dynein swings according to the ATPase states, which, presumably, generates force to carry cargos within a cell. The communication mechanism between the track-binding and ATPase domains of dynein is unique because the two helices that presumably slide with respect to each other work as coordinators for these domains. Details of the mechanism underlying the power stroke and interdomain communication were revealed through recent progress in the structural studies of myosin, kinesin and dynein.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Atherton J, Farabella I, Yu IM, Rosenfeld SS, Houdusse A, Topf M, Moores CA (2014) Conserved mechanisms of microtubule-stimulated ADP release, ATP binding, and force generation in transport kinesins. Elife 3:e03680

    Article  PubMed  PubMed Central  Google Scholar 

  • Banga I, Szent-Györgyi A (1941–1942) Preparation and properties of myosin A and B. In: Szent-Györgyi A (ed) Studies from the Institute of Medical Chemistry—University of Szeged, vol. 1. S. Karger AG, Basel, pp 5–15

  • Borisy GG, Taylor EW (1967) The mechanism of action of colchicine. Binding of colchincine-3H to cellular protein. J Cell Biol 34:525–533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brady ST (1985) A novel brain ATPase with properties expected for the fast axonal transport motor. Nature 317:73–75

    Article  CAS  PubMed  Google Scholar 

  • Burgess SA, Walker ML, Sakakibara H, Knight PJ, Oiwa K (2003) Dynein structure and power stroke. Nature 421:715–718

    Article  CAS  PubMed  Google Scholar 

  • Bustamante C, Chemla YR, Forde NR, Izhaky D (2004) Mechanical processes in biochemistry. Annu Rev Biochem 73:705–748

    Article  CAS  PubMed  Google Scholar 

  • Cao L, Wang W, Jiang Q, Wang C, Knossow M, Gigant B (2014) The structure of apo-kinesin bound to tubulin links the nucleotide cycle to movement. Nat Commun 5:5364

    Article  CAS  PubMed  Google Scholar 

  • Carter AP, Garbarino JE, Wilson-Kubalek EM, Shipley WE, Cho C, Milligan RA, Vale RD, Gibbons IR (2008) Structure and functional role of dynein’s microtubule-binding domain. Science 322:1691–1695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carter AP, Cho C, Jin L, Vale RD (2011) Crystal structure of the dynein motor domain. Science 331:1159–1165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cecchini M, Alexeev Y, Karplus M (2010) Pi release from myosin: a simulation analysis of possible pathways. Structure 18:458–470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Coureux PD, Wells AL, Ménétrey J, Yengo CM, Morris CA, Sweeney HL, Houdusse A (2003) A structural state of the myosin V motor without bound nucleotide. Nature 425:419–423

    Article  CAS  PubMed  Google Scholar 

  • Dominguez R, Freyzon Y, Trybus KM, Cohen C (1998) Crystal structure of a vertebrate smooth muscle myosin motor domain and its complex with the essential light chain: visualization of the pre-power stroke state. Cell 94:559–571

    Article  CAS  PubMed  Google Scholar 

  • Endres NF, Yoshioka C, Milligan RA, Vale RD (2006) A lever-arm rotation drives motility of the minus-end-directed kinesin Ncd. Nature 439:875–878

    Article  CAS  PubMed  Google Scholar 

  • Engelhardt WA, Ljubimowa MN (1939) Myosin and adenosine triphosphatase. Nature 144:668–669

    Article  CAS  Google Scholar 

  • Finer JT, Simmons RM, Spudich JA (1994) Single myosin molecule mechanics: piconewton forces and nanometre steps. Nature 368:113–119

    Article  CAS  PubMed  Google Scholar 

  • Fischer S, Windshügel B, Horak D, Holmes KC, Smith JC (2005) Structural mechanism of the recovery stroke in the myosin molecular motor. Proc Natl Acad Sci U S A 102:6873–6878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fliegauf M, Benzing T, Omran H (2007) When cilia go bad: cilia defects and ciliopathies. Nat Rev Mol Cell Biol 8:880–893

    Article  CAS  PubMed  Google Scholar 

  • Gee MA, Heuser JE, Vallee RB (1997) An extended microtubule-binding structure within the dynein motor domain. Nature 390:636–639

    Article  CAS  PubMed  Google Scholar 

  • Gennerich A, Carter AP, Reck-Peterson SL, Vale RD (2007) Force-induced bidirectional stepping of cytoplasmic dynein. Cell 131:952–965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gibbons IR, Rowe AJ (1965) Dynein: a protein with adenosine triphosphatase activity from cilia. Science 149:424–426

    Article  CAS  PubMed  Google Scholar 

  • Gibbons IR, Garbarino JE, Tan CE, Reck-Peterson SL, Vale RD, Carter AP (2005) The affinity of the dynein microtubule-binding domain is modulated by the conformation of its coiled-coil stalk. J Biol Chem 280:23960–23965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gigant B, Wang W, Dreier B, Jiang Q, Pecqueur L, Plückthun A, Wang C, Knossow M (2013) Structure of a kinesin–tubulin complex and implications for kinesin motility. Nat Struct Mol Biol 20:1001–1007

    Article  CAS  PubMed  Google Scholar 

  • Greenberg MJ, Shuman H, Ostap EM (2014) Inherent force-dependent properties of β-cardiac myosin contribute to the force–velocity relationship of cardiac muscle. Biophys J 107:L41–L44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Himmel DM, Gourinath S, Reshetnikova L, Shen Y, Szent-Györgyi AG, Cohen C (2002) Crystallographic findings on the internally uncoupled and near-rigor states of myosin: further insights into the mechanics of the motor. Proc Natl Acad Sci U S A 99:12645–12650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hirokawa N (1998) Kinesin and dynein superfamily proteins and the mechanism of organelle transport. Science 279:519–526

    Article  CAS  PubMed  Google Scholar 

  • Hirokawa N, Takemura R (2005) Molecular motors and mechanisms of directional transport in neurons. Nat Rev Neurosci 6:201–214

    Article  CAS  PubMed  Google Scholar 

  • Hirose K, Lockhart A, Cross RA, Amos LA (1995) Nucleotide-dependent angular change in kinesin motor domain bound to tubulin. Nature 376:277–279

    Article  CAS  PubMed  Google Scholar 

  • Hirose K, Akimaru E, Akiba T, Endow SA, Amos LA (2006) Large conformational changes in a kinesin motor catalyzed by interaction with microtubules. Mol Cell 23:913–923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoenger A, Sablin EP, Vale RD, Fletterick RJ, Milligan RA (1995) Three-dimensional structure of a tubulin–motor–protein complex. Nature 376:271–274

    Article  CAS  PubMed  Google Scholar 

  • Houdusse A, Szent-Györgyi AG, Cohen C (2000) Three conformational states of scallop myosin S1. Proc Natl Acad Sci U S A 97:11238–11243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Howard J, Hudspeth AJ, Vale RD (1989) Movement of microtubules by single kinesin molecules. Nature 342:154–158

    Article  CAS  PubMed  Google Scholar 

  • Huxley H, Hanson J (1954) Changes in the cross-striations of muscle during contraction and stretch and their structural interpretation. Nature 173:973–976

    Article  CAS  PubMed  Google Scholar 

  • Huxley AF, Niedergerke R (1954) Structural changes in muscle during contraction; interference microscopy of living muscle fibres. Nature 173:971–973

    Article  CAS  PubMed  Google Scholar 

  • Imai H, Shima T, Sutoh K, Walker ML, Knight PJ, Kon T, Burgess SA (2015) Direct observation shows superposition and large scale flexibility within cytoplasmic dynein motors moving along microtubules. Nat Commun 6:8179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamiya R (2002) Functional diversity of axonemal dyneins as studied in Chlamydomonas mutants. Int Rev Cytol 219:115–155

    Article  CAS  PubMed  Google Scholar 

  • Kato YS, Yagi T, Harris SA, Ohki SY, Yura K, Shimizu Y, Honda S, Kamiya R, Burgess SA, Tanokura M (2014) Structure of the microtubule-binding domain of flagellar dynein. Structure 22:1628–1638

    Article  CAS  PubMed  Google Scholar 

  • Kikkawa M, Hirokawa N (2006) High-resolution cryo-EM maps show the nucleotide binding pocket of KIF1A in open and closed conformations. EMBO J 25:4187–4194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kikkawa M, Ishikawa T, Wakabayashi T, Hirokawa N (1995) Three-dimensional structure of the kinesin head–microtubule complex. Nature 376:274–277

    Article  CAS  PubMed  Google Scholar 

  • Kikkawa M, Sablin EP, Okada Y, Yajima H, Fletterick RJ, Hirokawa N (2001) Switch-based mechanism of kinesin motors. Nature 411:439–445

    Article  CAS  PubMed  Google Scholar 

  • Kon T, Mogami T, Ohkura R, Nishiura M, Sutoh K (2005) ATP hydrolysis cycle-dependent tail motions in cytoplasmic dynein. Nat Struct Mol Biol 12:513–519

    Article  CAS  PubMed  Google Scholar 

  • Kon T, Oyama T, Shimo-Kon R, Imamula K, Shima T, Sutoh K, Kurisu G (2012) The 2.8 Å crystal structure of the dynein motor domain. Nature 484:345–350

    Article  CAS  PubMed  Google Scholar 

  • Kozielski F, Sack S, Marx A, Thormählen M, Schönbrunn E, Biou V, Thompson A, Mandelkow EM, Mandelkow E (1997) The crystal structure of dimeric kinesin and implications for microtubule-dependent motility. Cell 91:985–994

    Article  CAS  PubMed  Google Scholar 

  • Krendel M, Mooseker MS (2005) Myosins: tails (and heads) of functional diversity. Physiol 20:239–251

    Article  CAS  Google Scholar 

  • Kühner S, Fischer S (2011) Structural mechanism of the ATP-induced dissociation of rigor myosin from actin. Proc Natl Acad Sci U S A 108:7793–7798

    Article  PubMed  PubMed Central  Google Scholar 

  • Kull FJ, Endow SA (2013) Force generation by kinesin and myosin cytoskeletal motor proteins. J Cell Sci 126:9–19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kull FJ, Sablin EP, Lau R, Fletterick RJ, Vale RD (1996) Crystal structure of the kinesin motor domain reveals a structural similarity to myosin. Nature 380:550–555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lawrence CJ, Dawe RK, Christie KR, Cleveland DW, Dawson SC, Endow SA, Goldstein LS, Goodson HV, Hirokawa N, Howard J, Malmberg RL, McIntosh JR, Miki H, Mitchison TJ, Okada Y, Reddy AS, Saxton WM, Schliwa M, Scholey JM, Vale RD, Walczak CE, Wordeman L (2004) A standardized kinesin nomenclature. J Cell Biol 167:19–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Levy JR, Holzbaur EL (2006) Cytoplasmic dynein/dynactin function and dysfunction in motor neurons. Int J Dev Neurosci 24:103–111

    Article  CAS  PubMed  Google Scholar 

  • Makino T, Morii H, Shimizu T, Arisaka F, Kato Y, Nagata K, Tanokura M (2007) Reversible and irreversible coiled coils in the stalk domain of ncd motor protein. Biochemistry 46:9523–9532

    Article  CAS  PubMed  Google Scholar 

  • McDonald HB, Stewart RJ, Goldstein LS (1990) The kinesin-like ncd protein of drosophila is a minus end-directed microtubule motor. Cell 63:1159–1165

    Article  CAS  PubMed  Google Scholar 

  • Mermall V, Post PL, Mooseker MS (1998) Unconventional myosins in cell movement, membrane traffic, and signal transduction. Science 279:527–533

    Article  CAS  PubMed  Google Scholar 

  • Mizuno N, Narita A, Kon T, Sutoh K, Kikkawa M (2007) Three-dimensional structure of cytoplasmic dynein bound to microtubules. Proc Natl Acad Sci U S A 104:20832–20837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Neuwald AF, Aravind L, Spouge JL, Koonin EV (1999) AAA+: a class of chaperone-like ATPases associated with the assembly, operation, and disassembly of protein complexes. Genome Res 9:27–43

    CAS  PubMed  Google Scholar 

  • Odronitz F, Kollmar M (2007) Drawing the tree of eukaryotic life based on the analysis of 2,269 manually annotated myosins from 328 species. Genome Biol 8:R196

    Article  PubMed  PubMed Central  Google Scholar 

  • Parke CL, Wojcik EJ, Kim S, Worthylake DK (2010) ATP hydrolysis in Eg5 kinesin involves a catalytic two-water mechanism. J Biol Chem 285:5859–5867

    Article  CAS  PubMed  Google Scholar 

  • Popchock AR, Tseng KF, Wang P, Karplus PA, Xiang X, Qiu W (2017) The mitotic kinesin-14 KlpA contains a context-dependent directionality switch. Nat Commun 8:13999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rayment I, Rypniewski WR, Schmidt-Bäse K, Smith R, Tomchick DR, Benning MM, Winkelmann DA, Wesenberg G, Holden HM (1993a) Three-dimensional structure of myosin subfragment-1: a molecular motor. Science 261:50–58

    Article  CAS  PubMed  Google Scholar 

  • Rayment I, Holden HM, Whittaker M, Yohn CB, Lorenz M, Holmes KC, Milligan RA (1993b) Structure of the actin–myosin complex and its implications for muscle contraction. Science 261:58–65

    Article  CAS  PubMed  Google Scholar 

  • Redwine WB, Hernández-López R, Zou S, Huang J, Reck-Peterson SL, Leschziner AE (2012) Structural basis for microtubule binding and release by dynein. Science 337:1532–1536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reubold TF, Eschenburg S, Becker A, Kull FJ, Manstein DJ (2003) A structural model for actin-induced nucleotide release in myosin. Nat Struct Mol Biol 10:826–830

    Article  CAS  Google Scholar 

  • Rice S, Lin AW, Safer D, Hart CL, Naber N, Carragher BO, Cain SM, Pechatnikova E, Wilson-Kubalek EM, Whittaker M, Pate E, Cooke R, Taylor EW, Milligan RA, Vale RD (1999) A structural change in the kinesin motor protein that drives motility. Nature 402:778–784

    Article  CAS  PubMed  Google Scholar 

  • Roberts AJ, Numata N, Walker ML, Kato YS, Malkova B, Kon T, Ohkura R, Arisaka F, Knight PJ, Sutoh K, Burgess SA (2009) AAA+ ring and linker swing mechanism in the dynein motor. Cell 136:485–495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roberts AJ, Kon T, Knight PJ, Sutoh K, Burgess SA (2013) Functions and mechanics of dynein motor proteins. Nat Rev Mol Cell Biol 14:713–726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sablin EP, Kull FJ, Cooke R, Vale RD, Fletterick RJ (1996) Crystal structure of the motor domain of the kinesin-related motor ncd. Nature 380:555–559

    Article  CAS  PubMed  Google Scholar 

  • Sakakibara H, Kojima H, Sakai Y, Katayama E, Oiwa K (1999) Inner-arm dynein c of Chlamydomonas flagella is a single-headed processive motor. Nature 400:586–590

    Article  CAS  PubMed  Google Scholar 

  • Schmidt H, Gleave ES, Carter AP (2012) Insights into dynein motor domain function from a 3.3-Å crystal structure. Nat Struct Mol Biol 19:492–497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schmidt H, Zalyte R, Urnavicius L, Carter AP (2015) Structure of human cytoplasmic dynein-2 primed for its power stroke. Nature 518:435–438

    Article  CAS  PubMed  Google Scholar 

  • Schuh M (2011) An actin-dependent mechanism for long-range vesicle transport. Nat Cell Biol 13:1431–1436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shang Z, Zhou K, Xu C, Csencsits R, Cochran JC, Sindelar CV (2014) High-resolution structures of kinesin on microtubules provide a basis for nucleotide-gated force-generation. Elife 3:e04686

    Article  PubMed  PubMed Central  Google Scholar 

  • She ZY, Yang WX (2017) Molecular mechanisms of kinesin-14 motors in spindle assembly and chromosome segregation. J Cell Sci 130:2097–2110

    Article  CAS  PubMed  Google Scholar 

  • Straub FB (1943) Actin, II. Stud Inst Med Chem Univ Szeged III:23–37

    Google Scholar 

  • Sugi H, Minoda H, Inayoshi Y, Yumoto F, Miyakawa T, Miyauchi Y, Tanokura M, Akimoto T, Kobayashi T, Chaen S, Sugiura S (2008) Direct demonstration of the cross-bridge recovery stroke in muscle thick filaments in aqueous solution by using the hydration chamber. Proc Natl Acad Sci U S A 108:17396–17401

    Article  Google Scholar 

  • Thiede C, Fridman V, Gerson-Gurwitz A, Gheber L, Schmidt CF (2012) Regulation of bi-directional movement of single kinesin-5 Cin8 molecules. BioArchitecture 2:70–74

    Article  PubMed  PubMed Central  Google Scholar 

  • Uchimura S, Fujii T, Takazaki H, Ayukawa R, Nishikawa Y, Minoura I, Hachikubo Y, Kurisu G, Sutoh K, Kon T, Namba K, Muto E (2015) A flipped ion pair at the dynein–microtubule interface is critical for dynein motility and ATPase activation. J Cell Biol 208:211–222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vale RD, Reese TS, Sheetz MP (1985) Identification of a novel force-generating protein, kinesin, involved in microtubule-based motility. Cell 42:39–50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Veigel C, Schmitz S, Wang F, Sellers JR (2005) Load-dependent kinetics of myosin-V can explain its high processivity. Nat Cell Biol 7:861–869

    Article  CAS  PubMed  Google Scholar 

  • Vetter IR, Wittinghofer A (2001) The guanine nucleotide-binding switch in three dimensions. Science 294:1299–1304

    Article  CAS  PubMed  Google Scholar 

  • Walker RA, Salmon ED, Endow SA (1990) The Drosophila claret segregation protein is a minus-end directed motor molecule. Nature 347:780–782

    Article  CAS  PubMed  Google Scholar 

  • Weber KL, Sokac AM, Berg JS, Cheney RE, Bement WM (2004) A microtubule-binding myosin required for nuclear anchoring and spindle assembly. Nature 431:325–329

    Article  CAS  PubMed  Google Scholar 

  • Yamagishi M, Shigematsu H, Yokoyama T, Kikkawa M, Sugawa M, Aoki M, Shirouzu M, Yajima J, Nitta R (2016) Structural basis of backwards motion in kinesin-1-kinesin-14 chimera: implication for kinesin-14 motility. Structure 24:1322–1334

    Article  CAS  PubMed  Google Scholar 

  • Yang Y, Gourinath S, Kovács M, Nyitray L, Reutzel R, Himmel DM, O’Neall-Hennessey E, Reshetnikova L, Szent-Györgyi AG, Brown JH, Cohen C (2007) Rigor-like structures from muscle myosins reveal key mechanical elements in the transduction pathways of this allosteric motor. Structure 15:553–564

    Article  CAS  PubMed  Google Scholar 

  • Zhang P, Dai W, Hahn J, Gilbert SP (2015) Drosophila Ncd reveals an evolutionarily conserved powerstroke mechanism for homodimeric and heterodimeric kinesin-14s. Proc Natl Acad Sci U S A 112:6359–6364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Author notes

  1. Yusuke Kato and Takuya Miyakawa contributed equally to this work.

Authors and Affiliations

  1. Institute for Enzyme Research, Tokushima University, Tokushima, Japan

    Yusuke Kato

  2. Laboratory of Basic Science on Healthy Longevity, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan

    Takuya Miyakawa & Masaru Tanokura

Authors
  1. Yusuke Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takuya Miyakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masaru Tanokura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masaru Tanokura.

Ethics declarations

Conflict of interest

Yusuke Kato declares that he has no conflict of interest. Takuya Miyakawa declares that he has no conflict of interest. Masaru Tanokura declares that he has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by the authors.

Open access

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) as well as a link to the Creative Commons license, and indicate if changes were made.

Additional information

This article is part of a Special Issue on ‘Biomolecules to Bio-nanomachines - Fumio Arisaka 70th Birthday’ edited by Damien Hall, Junichi Takagi and Haruki Nakamura.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kato, Y., Miyakawa, T. & Tanokura, M. Overview of the mechanism of cytoskeletal motors based on structure. Biophys Rev 10, 571–581 (2018). https://doi.org/10.1007/s12551-017-0368-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12551-017-0368-1

Keywords

Search

Navigation