The way things move: Looking under the hood of molecular motor proteins

Science

Volumn 288, Issue 5463, 2000, Pages 88-

  Vale, Ronald D ^a   Milligan, Ronald A ^b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b SCRIPPS RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACTIN; ADENOSINE TRIPHOSPHATE; KINESIN; MESSENGER RNA; MYOSIN;

CELL DIVISION; CELL MOTION; MICROTUBULE ASSEMBLY; MOLECULAR DYNAMICS; MOLECULAR EVOLUTION; MUSCLE CONTRACTION; PRIORITY JOURNAL; PROTEIN ANALYSIS; REVIEW;

ACTINS; ADENOSINE TRIPHOSPHATE; ANIMALS; BINDING SITES; CYTOSKELETON; EVOLUTION, MOLECULAR; KINESIN; MICROTUBULES; MODELS, BIOLOGICAL; MODELS, MOLECULAR; MOLECULAR MOTOR PROTEINS; MYOSINS; PROTEIN CONFORMATION; PROTEIN STRUCTURE, SECONDARY;

EID: 0343415156     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.288.5463.88     Document Type: Review

References (79)

1. T. A. McMahon, Muscles, Reflexes and Locomotion (Princeton Univ. Press, Princeton, NJ, 1984).
2. J. Howard, A. J. Hudspeth, R. D. Vale, Nature 342, 154 (1989).
3. S. M. Block, L. S. Goldstein, B. J. Schnapp, Nature 348, 348 (1990).
4. J. T. Finer, R. M. Simmons, J. A. Spudich, Nature 368, 113 (1994).
5. A. Ishijima et al., Biochem. Biophys. Res. Commun. 199, 1057 (1994).
6. F. J. Kull, E. P. Sablin, R. Lau, R. J. Fletterick, R. D. Vale, Nature 380, 550 (1996).
7. R. D. Vale and R. J. Fletterick, Annu. Rev. Cell Dev. Biol. 13, 745 (1997).
8. F. J. Kull, R. D. Vale, R. J. Fletterick, J. Muscle Res. Cell Motil. 19, 877 (1998).
9. For a review, see V. Mermall, P. L. Post, M. S. Mooseker, Science 279, 527 (1998).
10. For a review, see L. S. B. Goldstein and A. V. Philp, Annu. Rev. Cell Dev. Biol. 15, 141 (1999).
11. H. E. Huxley, Science 164, 1356 (1969).
12. A. F. Huxley and R. M. Simmons, Nature 233, 533 (1971).
13. R. W. Lymn and E. W. Taylor, Biochemistry 10, 4617 (1971).
14. I. Rayment et al., Science 261, 50 (1993).
15. I. Rayment et al., Science 261, 58 (1993).
16. R. Dominguez, Y. Freyzon, K. M. Trybus, C. Cohen, Cell 94, 559 (1998).
17. In our view, both myosin and kinesin heads contain three comparable functional domains. (i) We use the term "catalytic core" to refer to the allosteric domain that contains the polymer and nucleotide binding regions and that contains the structurally overlapping elements in kinesins and myosins (first ∼700 and 320 amino acids in myosin and kinesin, respectively). The definition of catalytic core used here differs from the term "catalytic domain" in the myosin literature, which also includes the converter domain. (ii) The "converters" in myosins (18, 69) and "necks" in kinesins (7) are functionally analogous mechanical elements that extend from the catalytic core and undergo hinge-like motions during the ATPase cycle. (iii) The lever arm (long helix surrounded by light chains) in myosin and the second head/coiled coil in conventional kinesin both act to amplify the motions of the converter and neck linker, respectively.
18. A. Houdusse, V. N. Kalabokis, D. Himmel, A. G. Szent-Gyorgyi, C. Cohen, Cell 97, 459 (1999).
19. J. D. Jontes, E. M. Wilson-Kubalek, R. A. Milligan, Nature 378, 751 (1996).
20. K. A. Taylor et al., Cell 99, 421 (1999).
21. J. E. T. Corrie et al., Nature 400, 425 (1999).
22. T. Q. P. Uyeda, P. D. Abramson, J. A. Spudich, Proc. Natl. Acad. Sci. U.S.A. 93, 4459 (1996).
23. QuickTime movies showing animated models of myosin- and kinesin-based motility can be seen at Science Online (www.sciencemag.org/feature/data/ 1049155.shl).
24. K. Svoboda, C. F. Schmidt, B. J. Schnapp, S. M. Block, Nature 365, 721 (1993).
25. K. Visscher, M. J. Schnitzer, S. M. Block, Nature 400, 184 (1999).
26. S. Rice et al., Nature 402, 778 (1999).
27. Mutagenesis of 10 kinesin neck linker residues decreases motility by a factor of 200 to 500 but lowers microtubule-stimulated ATPase activity by only a factor of 3; this indicates that the neck linker is needed to drive efficient forward motion (70).
28. Because of the constraints imposed by binding the two heads of the kinesin dimer to the microtubule, the neck linker swings from the rearward to the forward-pointing position after ATP binding (Figs. 1 and 5). In the kinesin monomer, the detached neck linker can adopt multiple conformations (26), and the power stroke is likely to be smaller [on average 10 to 20 Å (30)].
29. E. Berliner, E. C. Young, K. Anderson, H. Mahtani, J. Gelles, Nature 373, 718 (1995).
30. W. O. Hancock and J. Howard, J. Cell Biol. 140, 1395 (1998).
31. J. Howard, Nature 389, 561 (1997).
32. D. D. Hackney, Annu. Rev. Physiol. 58, 731 (1996).
33. The work efficiencies of kinesin and myosin (each ∼50 to 60% efficient) are much greater than that of an automobile (∼10 to 15%).
34. A. J. Fisher et al., Biochemistry 34, 8960 (1995).
35. C. A. Smith and I. Rayment, Biochemistry 35, 5404 (1996).
36. The switch I and II loops in kinesin and myosin contain clusters of highly conserved residues that overlap in space when the catalytic cores are super-imposed (SSR motif in switch I and DxxGxE in switch II) (6).
37. Although the relay helix translates along its axis, the motion is more complex than that of a simple piston because there are tilt and rotational components as well (16).
38. A recent scallop myosin structure (with bound ADP) has been obtained that shows a third positioning of the relay helix, rigid relay loop, and converter/lever arm (18). How this structure fits into the mechanochemical cycle is unclear. The authors suggest that it may represent an ATP-rather than an ADP-bound state, whereas Cooke (71) has suggested that it represents a mechanically strained ADP-bound state of the motor.
39. 237), which is not seen in other kinesin structures. An analogous salt bridge is observed in myosin structures with ATP analogs.
40. S. Sack et al., Biochemistry 36, 16155 (1997).
41. E. P. Sablin et al., Nature 395, 813 (1998).
42. A. M. Gulick, H. Song, S. A. Endow, I. Rayment, Biochemistry 37, 1769 (1998).
43. S. A. Burgess, M. L. Walker, H. D. White, J. Trinick, J. Cell Biol. 139, 675 (1997).
44. J. E. Baker, I. Brust-Mascher, S. Ramachandran, L. E. LaConte, D. D. Thomas, Proc. Natl. Acad. Sci. U.S.A. 95, 2944 (1998).
45. C. Woehlke et al., Cell 90, 207 (1997).
46. The main polymer binding elements of kinesin (loop 12) and myosin (lower 50 kD domain) as well as "secondary" polymer binding sites (kinesin, loop 8/β5; myosin, upper 50 kD domain) are positioned similarly with respect to the common cores (45). As a result, the catalytic cores of kinesin and myosin are oriented in an overall similar position with respect to the axes of microtubule and actin filaments (Fig. 4A). Switch II and the relay helix are connected to the main polymer binding site, whereas switch I is located close to the secondary polymer binding site. These two switch regions probably affect the conformations of their adjacent polymer binding elements.
47. C Veigel et al., Nature 398, 530 (1999).
48. 325 in Fig. 2) can be seen at Science Online (www.sciencemag.org/feature/data/ 1049155.shl).
49. R. A. Walker, E. D. Salmon, S. A. Endow, Nature 347, 780 (1990).
50. H. B. McDonald, R. J. Stewart, L. S. Goldstein, Cell 63, 1159 (1990).
51. A. L Wells et al., Nature 401, 505 (1999).
52. K. Hirose, A. Lockhart, R. A. Cross, L. A. Amos, Proc. Natl. Acad. Sci. U.S.A. 93, 9539 (1996).
53. The ATP- and ADP-bound states are tight and weak binding microtubule states, respectively, for both Ned and conventional kinesin (59, 72). Like other myosins, the ADP-bound state is a tight binding state for myosin VI (51).
54. 2-termini of the catalytic core, both necks dock in a comparable configuration along the catalytic core and therefore may respond to similar cues from the active site (41). In contrast to kinesin, the two heads of Ncd are held together tightly by the neck coiled coil, which may restrain the Ncd dimer from forming a two-head-bound intermediate and moving processively along the microtubule.
55. Other examples of motors with different amplifiers include Toxoplasma myosin XIV, which lacks a long lever helix (73) and may operate using only a "converter-based" amplifier. Many types of kinesin necks also have evolved, some of which may stimulate mechanical disassembly of microtubules (74).
56. A. D. Mehta et al., Nature 400, 590 (1999).
57. R. J. Stewart, J. Semerjian, C. F. Schmidt, Eur. Biophys. J. 27, 353 (1998).
58. I. M. Crevel, A. Lockhart, R. A. Cross, J. Mol. Biol. 273, 160 (1997).
59. E. Pechatnikova and E. W. Taylor, Biophys. J. 77, 1003 (1999).
60. An interesting and unusual form of "processive" motion was discovered for a truncated kinesin KIF1A monomer, which displays biased one-dimensional diffusion along the microtubule (75). The monomeric motor domain of muscle myosin (S1) was also reported to take several consecutive steps along actin (76). The motility models proposed in those studies differ from the models presented here.
61. D. D. Hackney, Proc. Natl. Acad. Sci. U.S.A. 91, 5865 (1994).
62. Y.-Z. Ma and E. W. Taylor, J. Biol. Chem. 272, 724 (1997).
63. S. P. Gilbert, M. L. Moyer, K. A. Johnson, Biochemistry 37, 792 (1998).
64. -1 (62, 63).
65. L. Romberg, D. W. Pierce, R. D. Vale, J. Cell Biol. 140, 1407 (1998).
66. In the presence of actin, ADP release is the rate-limiting step in myosin V's ATPase cycle (67, 77). Thus, relative to muscle myosin, myosin V spends more time in a strongly bound state. This helps to maintain the two-head-bound intermediate by preventing the rapid release of the trailing head upon the completion of its power stroke (Fig. 5).
67. M. Rief et al., in preparation.
68. P. D. Boyer. Annu. Rev. Biochem. 66, 717 (1997).
69. A. Houdusse and C. Cohen, Structure 4, 21 (1996).
70. R. B. Case, S. Rice, C. L. Hart, B. Ly, R. D. Vale, Curr. Biol. 10, 157 (2000).
71. R. Cooke, Curr. Biol. 9, R773 (1999).
72. A. Lockhart and R. A. Cross, EMBO J. 13, 751 (1994).
73. M. B. Heintzelman and J. D. Schwartzman, J. mol. Biol. 271, 139 (1997).
74. A. Desai, S. Verma, T. J. Mitchison, C. E. Walczak, Cell 96, 69 (1999).
75. Y. Okada and N. Hirokawa, Science 283, 1152 (1999).
76. K. Kitamura, M. Tokunaga, A. H. Iwane, T. Yanagida, Nature 397, 129 (1999).
77. E. M. De La Cruz, A. L. Wells, S. S. Rosenfeld, E. M. Ostap, H. L. Sweeney, Proc. Natl. Acad. Sci. U.S.A. 96, 13726 (1999).
78. Unlike a robotic machine, the working stroke is likely to vary somewhat from one enzymatic cycle to the next, because the motor can begin its power stroke from a variety of conformations (not depicted in Fig. 4). For example, in myosin's prestroke state (ADP-Pi), the catalytic core can bind weakly to actin in several orientations, and the lever arm may be tilted at various angles relative to the core (20, 43, 44). Similarly, in a kinesin monomer, the neck linker is mobile in the pre-power stroke state (26). Thus, the power stroke in both kinesin and myosin appears to involve a "disordered-to-ordered" transition.
79. Because of space constraints, we can cite relatively few articles; we regret not being able to acknowledge many of the important contributions in this field. We thank G. Johnson, A. Lin, E. Sablin, and B. Sheehan for figure preparation. We are also grateful to C. Cohen, R. Cooke, R. Fletterick, S. Rice, L. Sweeney, E. Taylor, and K. Thorn for many stimulating discussions and for providing comments on the manuscript.