Cell Biochemistry and Biophysics

, Volume 54, Issue 1–3, pp 11–22 | Cite as

Mechanical Design of Translocating Motor Proteins

Review Paper


Translocating motors generate force and move along a biofilament track to achieve diverse functions including gene transcription, translation, intracellular cargo transport, protein degradation, and muscle contraction. Advances in single molecule manipulation experiments, structural biology, and computational analysis are making it possible to consider common mechanical design principles of these diverse families of motors. Here, we propose a mechanical parts list that include track, energy conversion machinery, and moving parts. Energy is supplied not just by burning of a fuel molecule, but there are other sources or sinks of free energy, by binding and release of a fuel or products, or similarly between the motor and the track. Dynamic conformational changes of the motor domain can be regarded as controlling the flow of free energy to and from the surrounding heat reservoir. Multiple motor domains are organized in distinct ways to achieve motility under imposed physical constraints. Transcending amino acid sequence and structure, physically and functionally similar mechanical parts may have evolved as nature’s design strategy for these molecular engines.


Kinesin Myosin DNA motor Chaperone Ribosome Mechanochemical cycle Fish model 



We thank Martin Karplus and anonymous reviewers for valuable input on the manuscript. This work was funded by the National Institute of Health grant R21NS058604.


  1. 1.
    Abbondanzieri, E. A., Greenleaf, W. J., Shaevitz, J. W., Landick, R., & Block, S. M. (2006). Direct observation of base-pair stepping by RNA polymerase. Nature, 438, 460–465.CrossRefGoogle Scholar
  2. 2.
    Adamovic, I., Mijailovich, S., & Karplus, M. (2008). The elastic properties of the structurally characterized myosin II S2 subdomain: A molecular dynamics and normal mode analysis. Biophysical journal, 94(10), 3779–3789.PubMedCrossRefGoogle Scholar
  3. 3.
    Ali, M. Y., Krementsova, E. B., Kennedy, G. G., Mahaffy, R., Pollard, T. D., Trybus, K. M., & Warshaw, D. M. (2007). Myosin Va maneuvers through actin intersections and diffuses along microtubules. Proceedings of the National Academy of Sciences of the United States of America, 104, 4332–4336.PubMedCrossRefGoogle Scholar
  4. 4.
    Ali, M. Y., Lu, H., Bookwalter, C. S., Warshaw, D. M., & Trybus, K. M. (2008). Myosin V and kinesin act as tethers to enhance each others’ processivity. Proceedings of the National Academy of Sciences of the United States of America, 105, 4691–4696.PubMedCrossRefGoogle Scholar
  5. 5.
    Asbury, C. L., Fehr, A. N., & Block, S. M. (2003). Kinesin moves by an asymmetric hand-over-hand mechanism. Science, 302, 2130–2134.PubMedCrossRefGoogle Scholar
  6. 6.
    Astumian, R. D. (1997). Thermodynamics and kinetics of a Brownian motor. Science, 276, 917–922.PubMedCrossRefGoogle Scholar
  7. 7.
    Block, S. M. (2007). Kinesin motor mechanics: Binding, stepping, tracking, gating, and limping. Biophysical journal, 92, 2986–2995.PubMedCrossRefGoogle Scholar
  8. 8.
    Block, S. M., Asbury, C. L., Shaevitz, J. W., & Lang, M. J. (2003). Probing the kinesin reaction cycle with a 2D optical force clamp. Proceedings of the National Academy of Sciences of the United States of America, 100, 2351–2356.PubMedCrossRefGoogle Scholar
  9. 9.
    Bochtler, M., Hartmann, C., Song, H. K., Bourenkov, G. P., Bartunik, H. D., & Huber, R. (2000). The structures of HslU and the ATP-dependent protease HslU-HslV. Nature, 403, 800–805.PubMedCrossRefGoogle Scholar
  10. 10.
    Brouhard, G. J., Stear, J. H., Noetzel, T. L., Al-Bassam, J., Kinoshita, K., Harrison, S. C., Howard, J., & Hyman, A. A. (2008). XMAP215 is a processive microtubule polymerase. Cell, 132, 79–88.PubMedCrossRefGoogle Scholar
  11. 11.
    Burgess, S. A., Walker, M. L., Sakakibara, H., Knight, P. J., & Oiwa, K. (2003). Dynein structure and power stroke. Nature, 421, 715–718.PubMedCrossRefGoogle Scholar
  12. 12.
    Bustamante, C., Chemla, Y. R., Forde, N. R., & Izhaky, D. (2004). Mechanical processes in biochemistry. Annual Review of Biochemistry, 73, 705–748.PubMedCrossRefGoogle Scholar
  13. 13.
    Büttner, K., Nehring, S., & Hopfner, K.-P. (2007). Structural basis for DNA duplex separation by a superfamily-2 helicase. Nature Structural and Molecular Biology, 14, 647–662.PubMedCrossRefGoogle Scholar
  14. 14.
    Chemla, Y. R., Aathavan, K., Michaelis, J., Grimes, S., Jardine, P. J., Anderson, D. L., & Bustamante, C. (2005). Mechanism of force generation of a viral DNA packaging motor. Cell, 122, 683–692.PubMedCrossRefGoogle Scholar
  15. 15.
    Chen, L. F., Winkler, H., Reedy, M. K., Reedy, M. C., & Taylor, K. A. (2002). Molecular modeling of averaged rigor crossbridges from tomograms of insect fight muscle. Journal of Structural Biology, 138, 92–104.PubMedCrossRefGoogle Scholar
  16. 16.
    Choe, S., & Sun, S. X. (2005). The elasticity of α-helices. The Journal of Chemical Physics, 122, 244912.PubMedCrossRefGoogle Scholar
  17. 17.
    Córdova, N. J., Ermentrout, B., & Oster, G. F. (1992). Dynamics of single-motor molecules: The thermal ratchet model. Proceedings of the National Academy of Sciences of the United States of America, 89, 339–343.PubMedCrossRefGoogle Scholar
  18. 18.
    Cruz, E. M. D. L., Ostap, E. M., & Sweeney, H. L. (2001). Kinetic mechanism and regulation of myosin VI. The Journal of Biological Chemistry, 276, 32373–32381.CrossRefGoogle Scholar
  19. 19.
    Dixit, R., Ross, J. L., Goldman, Y. E., & Holzbaur, E. L. F. (2008). Differential regulation of dynein and kinesin motor proteins by tau. Science, 319, 1086–1089.PubMedCrossRefGoogle Scholar
  20. 20.
    Endres, N. F., Yoshioka, C., Milligan, R. A., & Vale, R. D. (2006). A lever-arm rotation drives motility of the minus-end-directed kinesin Ncd. Nature, 439, 875–878.PubMedCrossRefGoogle Scholar
  21. 21.
    Forkey, J. N., Quinlan, M. E., & Goldman, Y. E. (2000). Protein structural dynamics by single-molecule fuorescence polarization. Progress in Biophysics and Molecular Biology, 74, 1–35.PubMedCrossRefGoogle Scholar
  22. 22.
    Gao, Y. Q., Yang, W., & Karplus, M. (2005). A structure-based model for the synthesis and hydrolysis of ATP by F1-ATPase. Cell, 123, 195–205.PubMedCrossRefGoogle Scholar
  23. 23.
    Geeves, M. A. & Holmes, K. C. (2005). The molecular mechanism of muscle contraction. Advances in Protein Chemistry, 71, 161–193.PubMedCrossRefGoogle Scholar
  24. 24.
    Gelis, I., Bonvin, A. M., Keramisanou, D., Koukaki, M., Gouridis, G., Karamanou, S., Economou, A., & Kalodimos, C. G. (2007). Structural basis for signal-sequence recognition by the translocase motor SecA as determined by NMR. Cell, 131, 756–769.PubMedCrossRefGoogle Scholar
  25. 25.
    Gelles, J., & Landick, R. (1998). RNA polymerase as a molecular motor. Cell, 93, 13–16.PubMedCrossRefGoogle Scholar
  26. 26.
    Gennerich, A., Carter, A. P., Reck-Peterson, S. L., & Vale, R. D. (2007). Force-induced bidirectional stepping of cytoplasmic dynein. Cell, 131, 952–965.PubMedCrossRefGoogle Scholar
  27. 27.
    Goode, B. L., & Eck, M. J. (2007). Mechanism and function of formins in the control of actin assembly. Annual Review of Biochemistry, 76, 593–627.PubMedCrossRefGoogle Scholar
  28. 28.
    Hartl, F. U., & Hayer-Hartl, M. (2002). Molecular chaperones in the cytosol: From nascent chain to folded protein. Science, 295, 1852–1858.PubMedCrossRefGoogle Scholar
  29. 29.
    Hasson, T., & Cheney, R. E. (2001). Mechanisms of motor protein reversal. Current Opinion in Cell Biology, 13, 29–35.PubMedCrossRefGoogle Scholar
  30. 30.
    Hengge, R., & Bukau, B. (2003). Proteolysis in prokaryotes: Protein quality control and regulatory principles. Molecular Microbiology, 49, 1451–1462.PubMedCrossRefGoogle Scholar
  31. 31.
    Higashi-Fujime, S., Ishikawa, R., Iwasawa, H., Kagami, O., Kurimoto, E., Kohama, K., & Hozumi, T. (1995). The fastest-actin-based motor protein from the green algae, Chara, and its distinct mode of interaction with actin. FEBS Letters, 375, 151–154.PubMedCrossRefGoogle Scholar
  32. 32.
    Howard, J. (1997). Molecular motors: Structural adaptations to cellular functions. Nature, 389, 561–567.PubMedCrossRefGoogle Scholar
  33. 33.
    Howard, J. (2001). Mechanics of motor proteins and the cytoskeleton. Sinauer: Sunderland, MA.Google Scholar
  34. 34.
    Humphrey, W., Dalke, A., & Schulten, K. (1996). VMD-Visual molecular dynamics. Journal of Molecular Graphics, 14, 33–38.PubMedCrossRefGoogle Scholar
  35. 35.
    Hwang, W., Lang, M. J., & Karplus, M. (2008). Force generation in kinesin hinges on cover-neck bundle formation. Structure, 16, 62–71.PubMedCrossRefGoogle Scholar
  36. 36.
    Jaud, J., Bathe, F., Schliwa, M., Rief, M., & Woehlke, G. (2006). Flexibility of the neck domain enhances Kinesin-1 motility under load. Biophysical Journal, 91, 1407–1412.PubMedCrossRefGoogle Scholar
  37. 37.
    Keller, D., & Bustamante, C. (2000). The mechanochemistry of molecular motors. Biophysical Journal, 78, 541–556.PubMedCrossRefGoogle Scholar
  38. 38.
    Khalil, A. S., Appleyard, D. C., Labno, A. K., Georges, A. Karplus, M., Belcher, A. M., Hwang, W., & Lang, M. J. (2008). Kinesin’s cover-neck bundle folds forward to generate force. Proceedings of the National Academy of Sciences of the United States of America, 105, 19247–19252.PubMedCrossRefGoogle Scholar
  39. 39.
    Kikkawa, M. (2008). The role of microtubules in processive kinesin movement. Trends in Cell Biology, 18, 128–135.PubMedCrossRefGoogle Scholar
  40. 40.
    Kikkawa, M., Sablin, E. P., Okada, Y., Yajima, H., Fletterick, R. J., & Hirokawa, N. (2001). Switch-based mechanism of kinesin motors. Nature, 411, 439–445.PubMedCrossRefGoogle Scholar
  41. 41.
    Kolomeisky, A. B., & Fisher, M. E. (2007). Molecular motors: A theorist’s perspective. Annual Review of Physical Chemistry, 58, 675–695.PubMedCrossRefGoogle Scholar
  42. 42.
    Kovall, R., & Matthews, B. W. (1997). Toroidal structure of λ-exonuclease. Science, 277, 1824–1827.PubMedCrossRefGoogle Scholar
  43. 43.
    Kull, F. J., Sablin, E. P., Lau, R., Fletterick, R. J., & Vale, R. D. (1996). Crystal structure of the kinesin motor domain reveals a structural similarity to myosin. Nature, 380, 550–555.PubMedCrossRefGoogle Scholar
  44. 44.
    Kural, C., Kim, H., Syed, S., Goshima, G., Gelfand, V. I., & Selvin, P. R. (2005). Kinesin and dynein move a peroxisome in vivo: A tug-of-war or coordinated movement?. Science, 308, 1469–1472.PubMedCrossRefGoogle Scholar
  45. 45.
    Kuzminov, A. (1999). Recombinational repair of DNA damage in Escherichia coli and bacteriophage λ. Microbiology and Molecular Biology Reviews, 63, 751–813.PubMedGoogle Scholar
  46. 46.
    Lakkaraju, S. K., & Hwang, W. (2009). Critical buckling length versus persistence length: What governs biofilament conformation?. Physical Review Letters, 102, 118102.PubMedCrossRefGoogle Scholar
  47. 47.
    Li, H., DeRosier, D. J., Nicholson, W. V., Nogales, E., & Downing, K. H. (2002). Microtubule structure at 8 Å resolution. Structure, 10, 1317–1328.PubMedCrossRefGoogle Scholar
  48. 48.
    Liu, J., Taylor, D. W., Krementsova, E. B., Trybus, K. M., & Taylor, K. A. (2006). Three-dimensional structure of the myosin V inhibited state by cryoelectron tomography. Nature, 442, 208–211.PubMedGoogle Scholar
  49. 49.
    Lymn, R. W., & Taylor, E. W. (1971). Mechanism of adenosine triphosphate hydrolysis by actomyosin. Biochemistry, 10, 4617–4624.PubMedCrossRefGoogle Scholar
  50. 50.
    Ma, Y. -Z., & Taylor, E. W. (1995). Kinetic mechanism of kinesin motor domain. Biochemistry, 34, 13233–13241.PubMedCrossRefGoogle Scholar
  51. 51.
    Mallik, R., Carter, B. C., Lex, S. A., King, S. J., & Gross, S. P. (2004). Cytoplasmic dynein functions as a gear in response to load. Nature, 427, 649–652.PubMedCrossRefGoogle Scholar
  52. 52.
    Mehta, A. D., Rock, R. S., Rief, M., Spudich, J. A., Mooseker, M. S., & Cheney, R. E. (1999). Myosin-V is a processive actin-based motor. Nature, 400, 590–593.PubMedCrossRefGoogle Scholar
  53. 53.
    Ménétrey, J., Bahloul, A., Wells, A. L., Yengo, C. M., Morris, C. A., Sweeney, H. L., & Houdusse, A. (2005). The structure of the myosin VI motor reveals the mechanism of directionality reversal. Nature, 435, 779–785.PubMedCrossRefGoogle Scholar
  54. 54.
    Mori, T., Vale, R. D., & Tomishige, M. (2007). How kinesin waits between steps. Nature, 450, 750–755.PubMedCrossRefGoogle Scholar
  55. 55.
    Moyer, M. L., Gilbert, S. P., & Johnson, K. A. (1998). Pathway of ATP hydrolysis by monomeric and dimeric kinesin. Biochemistry, 37, 800–813.PubMedCrossRefGoogle Scholar
  56. 56.
    Nitta, R., Kikkawa, M., Okada, Y., & Hirokawa, N. (2004). KIF1A alternately uses two loops to bind microtubules. Science, 305, 678–683.PubMedCrossRefGoogle Scholar
  57. 57.
    Oster, G., & Wang, H. (2003). How protein motors convert chemical energy into mechanical work. In Manfred Schliwa, (Ed.), Molecular motors (Chap. 8). Weinheim, Germany: Wiley-VCH.Google Scholar
  58. 58.
    Park, J., Kahng, B., Kamm, R. D., & Hwang, W. (2006). Atomistic simulation approach to a continuum description of self-assembled β-sheet filaments. Biophysical Journal, 90, 2510–2524.PubMedCrossRefGoogle Scholar
  59. 59.
    Rice, S., Cui, Y., Sindelar, C., Naber, N., Matuska, M., Vale, R., & Cooke, R. (2003). Thermodynamic properties of the kinesin neck-region docking to the catalytic core. Biophysical Journal, 84, 1844–1854.PubMedCrossRefGoogle Scholar
  60. 60.
    Rice, S., Lin, A. W., Safer, D., Hart, C. L., Naberk, N., Carragher, B. O., Cain, S. M., Pechatnikova, E., Wilson-Kubalek, E. M. Whittaker, M., Pate, E., Cooke, R., Taylor, E. W., Milligan, R. A., & Vale, R. D. (1999). A structural change in the kinesin motor protein that drives motility. Nature, 402, 778–784.PubMedCrossRefGoogle Scholar
  61. 61.
    Rock, R. S., Rice, S. E., Wells, A. L., Purcell, T. J., Spudich, J. A., & Sweeney, H. L. (2001). Myosin VI is a processive motor with a large step size. Proceedings of the National Academy of Sciences of the United States of America, 98, 13655–13659.PubMedCrossRefGoogle Scholar
  62. 62.
    Rosenfeld, S. S., Jefferson, G. M., & King, P. H. (2001). ATP reorients the neck linker of kinesin in two sequential steps. The Journal of Biological Chemistry, 276, 40167–40174.PubMedCrossRefGoogle Scholar
  63. 63.
    Rosenfeld, S. S., Xing, J., Jefferson, G. M., Cheung, H. C., & King, P. H. (2002). Measuring kinesin’s first step. The Journal of Biological Chemistry, 277, 36731–36739.PubMedCrossRefGoogle Scholar
  64. 64.
    Ross, J. L., Wallace, K., Shuman, H., Goldman, Y. E., & Holzbaur, E. L. (2006). Processive bidirectional motion of dynein-dynactin complexes in vitro. Nature Cell Biology, 8, 562–570.PubMedCrossRefGoogle Scholar
  65. 65.
    Sablin, E. P., & Fletterick, R. J. (2004). Coordination between motor domains in processive kinesins. The Journal of Biological Chemistry, 279, 15707–15710.PubMedCrossRefGoogle Scholar
  66. 66.
    Schmidt, M., Lupas, A. N., & Finley, D. (1999). Structure and mechanism of ATP-dependent proteases. Current Opinion in Chemical Biology, 3, 584–591.PubMedCrossRefGoogle Scholar
  67. 67.
    Seidel, R., & Dekker, C. (2007). Single-molecule studies of nucleic acid motors. Current Opinion in Structural Biology, 17, 80–86.PubMedCrossRefGoogle Scholar
  68. 68.
    Selmer, M., Dunham, C. M., Murphy IV, F. V., Weixlbaumer, A., Petry, S., Kelley, A. C., Weir, J. R., & Ramakrishnan, V. (2006). Structure of the 70S ribosome complexed with mRNA and tRNA. Science, 313, 1935–1942.PubMedCrossRefGoogle Scholar
  69. 69.
    Sindelar, C. V., Budny, M. J., Rice, S., Naber, N., Fletterick, R., & Cooke, R. (2002). Two conformations in the human kinesin power stroke defined by X-ray crystallography and EPR spectroscopy. Nature Structural Biology, 9, 844–848.PubMedGoogle Scholar
  70. 70.
    Sindelar, C. V., & Downing, K. H. (2007). The beginning of kinesin’s force-generating cycle visualized at 9-Å resolution. The Journal of Cell Biology, 177, 377–385.PubMedCrossRefGoogle Scholar
  71. 71.
    Smith, D. E., Tans, S. J., Smith, S. B., Grimes, S., Anderson, D. L., & Bustamante, C. (2001). The bacteriophage ϕ29 portal motor can package DNA against a large internal force. Nature, 413, 748–752.PubMedCrossRefGoogle Scholar
  72. 72.
    Sosa, H., Peterman, E. J., Moerner, W., & Goldstein, L. S. (2001). ADP-induced rocking of the kinesin motor domain revealed by single-molecule fluorescence polarization microscopy. Nature Structural Biology, 8, 540–544.PubMedCrossRefGoogle Scholar
  73. 73.
    Svoboda, K., Mitra, P. P., & Block, S. M. (1994). Fluctuation analysis of motor protein movement and single enzyme kinetics. Proceedings of the National Academy of Sciences of the United States of America, 91, 11782–11786.PubMedCrossRefGoogle Scholar
  74. 74.
    Svoboda, K., Schmidt, C. F., Schnapp, B. J., & Block, S. M. (1993). Direct observation of kinesin stepping by optical trapping interferometry. Nature, 365, 721–727.PubMedCrossRefGoogle Scholar
  75. 75.
    Taniguchi, Y., Nishiyama, M., Ishii, Y., & Yanagida, T. (2005). Entropy rectifies the Brownian steps of kinesin. Nature Chemical Biology, 1, 342–347.PubMedCrossRefGoogle Scholar
  76. 76.
    Uchimura, S., Oguchi, Y., Katsuki, M., Usui, T., Osada, H., Nikawa, J., Ishiwata, S., & Muto, E. (2006). Identification of a strong binding site for kinesin on the microtubule using mutant analysis of tubulin. The EMBO Journal, 25, 5932–5941.PubMedCrossRefGoogle Scholar
  77. 77.
    Uyeda, T. Q. P., Abramson, P. D., & Spudich, J. A. (1996). The neck region of the myosin motor domain acts as a lever arm to generate movement. Proceedings of the National Academy of Sciences of the United States of America, 93, 4459–4464.PubMedCrossRefGoogle Scholar
  78. 78.
    Vale, R. D. (2000). AAA proteins: Lords of the ring. The Journal of Cell Biology, 150, F13–F19.PubMedCrossRefGoogle Scholar
  79. 79.
    Vale, R. D. (2003). The molecular motor toolbox for intracellular transport. Cell, 112, 467–480.PubMedCrossRefGoogle Scholar
  80. 80.
    Vale, R. D., & Milligan, R. A. (2000). The way things move: Looking under the hood of molecular motor proteins. Science, 288, 88–95.PubMedCrossRefGoogle Scholar
  81. 81.
    Van Kampen, N. G. (1992). Stochastic processes in physics and chemistry. Elsevier: Netherlands.Google Scholar
  82. 82.
    van Oijen, A. M., Blainey, P. C., Crampton, D. J., Richardson, C. C., Ellenberger, T., & Xie, X. S. (2003). Single-molecule kinetics of λ exonuclease reveal base dependence and dynamic disorder. Science, 301, 1235–1238.PubMedCrossRefGoogle Scholar
  83. 83.
    Veigel, C., Wang, F., Bartoo, M. L., Sellers, J. R., & Molloy, J. E. (2002). The gated gait of the processive molecular motor, myosin V. Nature Cell Biology, 4, 59–65.PubMedCrossRefGoogle Scholar
  84. 84.
    Wade, R. H., & Kozielski, F. (2000). Structural links to kinesin directionality and movement. Nature Structural Biology, 7, 456–460.PubMedCrossRefGoogle Scholar
  85. 85.
    Wang, D., Bushnell, D. A., Westover, K. D., Kaplan, C. D., & Kornberg, R. D. (2006). Structural basis of transcription: Role of the trigger loop in substrate specificity and catalysis. Cell, 127, 941–954.PubMedCrossRefGoogle Scholar
  86. 86.
    Wang, H., & Oster, G. (2002). Ratchets, power strokes, and molecular motors. Applied Physics A, 75, 315–323.CrossRefGoogle Scholar
  87. 87.
    Wang, H. -Y., Elston, T., Mogilner, A., & Oster, G. (1998). Force generation in RNA polymerase. Biophysical journal, 74, 1186–1202.PubMedCrossRefGoogle Scholar
  88. 88.
    Wang, J. (2004). Nucleotide-dependent domain motions within rings of the RecA/AAA+ superfamily. Journal of Structural Biology, 148, 259–267.PubMedCrossRefGoogle Scholar
  89. 89.
    Wang, M. D., Schnitzer, M. J., Yin, H., Landick, R., Gelles, J., & Block S. M. (1998). Force and velocity measured for single molecules of RNA polymerase. Science, 282, 902–907.PubMedCrossRefGoogle Scholar
  90. 90.
    Weisenseel, J. P., Reddy, G. R., Marnett, L. J., & Stone, M. P. (2002). Structure of an oligodeoxynucleotide containing a 1,N-propanodeoxyguanosine adduct positioned in a palindrome derived from the Salmonella typhimurium hisD3052 gene: Hoogsteen pairing at pH 5.2. Chemical Research in Toxicology, 15, 127–139.PubMedCrossRefGoogle Scholar
  91. 91.
    Yildiz, A., Tomishige, M., Gennerich, A., & Vale, R. D. (2008). Intramolecular strain coordinates kinesin stepping behavior along microtubules. Cell, 134, 1030–1041.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  1. 1.Department of Biomedical EngineeringTexas A&M UniversityCollege StationUSA
  2. 2.Department of Biological Engineering and Department of Mechanical Engineering Massachusetts Institute of TechnologyCambridgeUSA

Personalised recommendations