Skip to main content
SpringerLink
Log in

Bidirectional motility of kinesin-5 motor proteins: structural determinants, cumulative functions and physiological roles

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Mitotic kinesin-5 bipolar motor proteins perform essential functions in mitotic spindle dynamics by crosslinking and sliding antiparallel microtubules (MTs) apart within the mitotic spindle. Two recent studies have indicated that single molecules of Cin8, the Saccharomyces cerevisiae kinesin-5 homolog, are minus end-directed when moving on single MTs, yet switch directionality under certain experimental conditions (Gerson-Gurwitz et al., EMBO J 30:4942–4954, 2011; Roostalu et al., Science 332:94–99, 2011). This finding was unexpected since the Cin8 catalytic motor domain is located at the N-terminus of the protein, and such kinesins have been previously thought to be exclusively plus end-directed. In addition, the essential intracellular functions of kinesin-5 motors in separating spindle poles during mitosis can only be accomplished by plus end-directed motility during antiparallel sliding of the spindle MTs. Thus, the mechanism and possible physiological role of the minus end-directed motility of kinesin-5 motors remain unclear. Experimental and theoretical studies from several laboratories in recent years have identified additional kinesin-5 motors that are bidirectional, revealed structural determinants that regulate directionality, examined the possible mechanisms involved and have proposed physiological roles for the minus end-directed motility of kinesin-5 motors. Here, we summarize our current understanding of the remarkable ability of certain kinesin-5 motors to switch directionality when moving along MTs.

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

Similar content being viewed by others

References

  1. Boettcher B, Barral Y (2013) The cell biology of open and closed mitosis. Nucleus 4:160–165

    Article  PubMed  PubMed Central  Google Scholar 

  2. Lim HH, Zhang T, Surana U (2009) Regulation of centrosome separation in yeast and vertebrates: common threads. Trends Cell Biol 19:325–333

    Article  CAS  PubMed  Google Scholar 

  3. Sazer S, Lynch M, Needleman D (2014) Deciphering the evolutionary history of open and closed mitosis. Curr Biol 24:R1099–R1103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zheng Y (2010) A membranous spindle matrix orchestrates cell division. Nat Rev Mol Cell Biol 11:529–535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mitchison T, Kirschner M (1984) Dynamic instability of microtubule growth. Nature 312:237–242

    Article  CAS  PubMed  Google Scholar 

  6. Walker RA, O’Brien ET, Pryer NK, Soboeiro MF, Voter WA, Erickson HP, Salmon ED (1988) Dynamic instability of individual microtubules analyzed by video light microscopy: rate constants and transition frequencies. J Cell Biol 107:1437–1448

    Article  CAS  PubMed  Google Scholar 

  7. Dumont S, Mitchison TJ (2009) Force and length in the mitotic spindle. Curr Biol 19:R749–R761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Prosser SL, Pelletier L (2017) Mitotic spindle assembly in animal cells: a fine balancing act. Nat Rev Mol Cell Biol 18:187–201

    Article  CAS  PubMed  Google Scholar 

  9. Maddox P, Straight A, Coughlin P, Mitchison TJ, Salmon ED (2003) Direct observation of microtubule dynamics at kinetochores in Xenopus extract spindles: implications for spindle mechanics. J Cell Biol 162:377–382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. McDonald KL, O’Toole ET, Mastronarde DN, McIntosh JR (1992) Kinetochore microtubules in PTK cells. J Cell Biol 118:369–383

    Article  CAS  PubMed  Google Scholar 

  11. Grill SW, Howard J, Schaffer E, Stelzer EH, Hyman AA (2003) The distribution of active force generators controls mitotic spindle position. Science 301:518–521

    Article  CAS  PubMed  Google Scholar 

  12. O’Connell CB, Wang YL (2000) Mammalian spindle orientation and position respond to changes in cell shape in a dynein-dependent fashion. Mol Biol Cell 11:1765–1774

    Article  PubMed  PubMed Central  Google Scholar 

  13. Sheeman B, Carvalho P, Sagot I, Geiser J, Kho D, Hoyt MA, Pellman D (2003) Determinants of S. cerevisiae dynein localization and activation: implications for the mechanism of spindle positioning. Curr Biol 13:364–372

    Article  CAS  PubMed  Google Scholar 

  14. Mastronarde DN, McDonald KL, Ding R, McIntosh JR (1993) Interpolar spindle microtubules in PTK cells. J Cell Biol 123:1475–1489

    Article  CAS  PubMed  Google Scholar 

  15. Nazarova E, O’Toole E, Kaitna S, Francois P, Winey M, Vogel J (2013) Distinct roles for antiparallel microtubule pairing and overlap during early spindle assembly. Mol Biol Cell 24:3238–3250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Winey M, Mamay CL, O’Toole ET, Mastronarde DN, Giddings TH Jr, McDonald KL, McIntosh JR (1995) Three-dimensional ultrastructural analysis of the Saccharomyces cerevisiae mitotic spindle. J Cell Biol 129:1601–1615

    Article  CAS  PubMed  Google Scholar 

  17. Kapoor TM (2017) Metaphase spindle assembly. Biology (Basel) 6:E8

    Google Scholar 

  18. Tanenbaum ME, Medema RH (2010) Mechanisms of centrosome separation and bipolar spindle assembly. Dev Cell 19:797–806

    Article  CAS  PubMed  Google Scholar 

  19. Blangy A, Arnaud L, Nigg EA (1997) Phosphorylation by p34cdc2 protein kinase regulates binding of the kinesin-related motor HsEg5 to the dynactin subunit p150. J Biol Chem 272:19418–19424

    Article  CAS  PubMed  Google Scholar 

  20. Hoyt MA, He L, Loo KK, Saunders WS (1992) Two Saccharomyces cerevisiae kinesin-related gene products required for mitotic spindle assembly. J Cell Biol 118:109–120

    Article  CAS  PubMed  Google Scholar 

  21. Mayer TU, Kapoor TM, Haggarty SJ, King RW, Schreiber SL, Mitchison TJ (1999) Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 286:971–974

    Article  CAS  PubMed  Google Scholar 

  22. Rincon SA, Lamson A, Blackwell R, Syrovatkina V, Fraisier V, Paoletti A, Betterton MD, Tran PT (2017) Kinesin-5-independent mitotic spindle assembly requires the antiparallel microtubule crosslinker Ase1 in fission yeast. Nat Commun 8:15286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Roof DM, Meluh PB, Rose MD (1992) Kinesin-related proteins required for assembly of the mitotic spindle. J Cell Biol 118:95–108

    Article  CAS  PubMed  Google Scholar 

  24. Cytrynbaum EN, Scholey JM, Mogilner A (2003) A force balance model of early spindle pole separation in Drosophila embryos. Biophys J 84:757–769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gönczy P, Pichler S, Kirkham M, Hyman AA (1999) Cytoplasmic dynein is required for distinct aspects of MTOC positioning, including centrosome separation, in the one cell stage Caenorhabditis elegans embryo. J Cell Biol 147:135–150

    Article  PubMed  PubMed Central  Google Scholar 

  26. Robinson JT, Wojcik EJ, Sanders MA, McGrail M, Hays TS (1999) Cytoplasmic dynein is required for the nuclear attachment and migration of centrosomes during mitosis in Drosophila. J Cell Biol 146:597–608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Salina D, Bodoor K, Eckley DM, Schroer TA, Rattner JB, Burke B (2002) Cytoplasmic dynein as a facilitator of nuclear envelope breakdown. Cell 108:97–107

    Article  CAS  PubMed  Google Scholar 

  28. Sharp DJ, Rogers GC, Scholey JM (2000) Cytoplasmic dynein is required for poleward chromosome movement during mitosis in Drosophila embryos. Nat Cell Biol 2:922–930

    Article  CAS  PubMed  Google Scholar 

  29. Vaisberg EA, Koonce MP, McIntosh JR (1993) Cytoplasmic dynein plays a role in mammalian mitotic spindle formation. J Cell Biol 123:849–858

    Article  CAS  PubMed  Google Scholar 

  30. Cleveland DW, Mao Y, Sullivan KF (2003) Centromeres and kinetochores: from epigenetics to mitotic checkpoint signaling. Cell 112:407–421

    Article  CAS  PubMed  Google Scholar 

  31. Diogo V, Teixeira J, Silva PM, Bousbaa H (2016) Spindle assembly checkpoint as a potential target in colorectal cancer: current status and future perspectives. Clin Colorectal Cancer 23:30080–30089

    Google Scholar 

  32. Musacchio A (2015) The molecular biology of spindle assembly checkpoint signaling dynamics. Curr Biol 25:R1002–R1018

    Article  CAS  PubMed  Google Scholar 

  33. Tan AL, Rida PC, Surana U (2005) Essential tension and constructive destruction: the spindle checkpoint and its regulatory links with mitotic exit. Biochem J 386:1–13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Alexandru G, Uhlmann F, Mechtler K, Poupart MA, Nasmyth K (2001) Phosphorylation of the cohesin subunit Scc1 by Polo/Cdc5 kinase regulates sister chromatid separation in yeast. Cell 105:459–472

    Article  CAS  PubMed  Google Scholar 

  35. D’Amours D, Amon A (2004) At the interface between signaling and executing anaphase—Cdc14 and the FEAR network. Genes Dev 18:2581–2595

    Article  PubMed  CAS  Google Scholar 

  36. Surana U, Amon A, Dowzer C, McGrew J, Byers B, Nasmyth K (1993) Destruction of the CDC28/CLB mitotic kinase is not required for the metaphase to anaphase transition in budding yeast. EMBO J 12:1969–1978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Asbury CL (2017) Anaphase A: disassembling microtubules move chromosomes toward spindle poles. Biology (Basel) 6:E15

    Google Scholar 

  38. Meadows JC, Millar JB (2015) Sharpening the anaphase switch. Biochem Soc Trans 43:19–22

    Article  CAS  PubMed  Google Scholar 

  39. Scholey JM, Civelekoglu-Scholey G, Brust-Mascher I (2016) Anaphase B. Biology (Basel) 5:E51

    Google Scholar 

  40. Winey M, Bloom K (2012) Mitotic spindle form and function. Genetics 190:1197–1224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Barlan K, Gelfand VI (2017) Microtubule-based transport and the distribution, tethering, and organization of organelles. Cold Spring Harb Perspect Biol 9:a025817

    Article  PubMed  PubMed Central  Google Scholar 

  42. Barton NR, Goldstein LS (1996) Going mobile: microtubule motors and chromosome segregation. Proc Natl Acad Sci USA 93:1735–1742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bloom GS, Endow SA (1995) Motor proteins 1: kinesins. Protein Profile 2:1105–1171

    CAS  PubMed  Google Scholar 

  44. Hirokawa N, Noda Y, Okada Y (1998) Kinesin and dynein superfamily proteins in organelle transport and cell division. Curr Opin Cell Biol 10:60–73

    Article  CAS  PubMed  Google Scholar 

  45. Lu W, Gelfand VI (2017) Moonlighting motors: kinesin, dynein, and cell polarity. Trends Cell Biol 27:505–514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Milisav I (1998) Dynein and dynein-related genes. Cell Motil Cytoskelet 39:261–272

    Article  CAS  Google Scholar 

  47. Morfini G, Schmidt N, Weissmann C, Pigino G, Kins S (2016) Conventional kinesin: biochemical heterogeneity and functional implications in health and disease. Brain Res Bull 126:347–353

    Article  CAS  PubMed  Google Scholar 

  48. Cole DG, Saxton WM, Sheehan KB, Scholey JM (1994) A “slow” homotetrameric kinesin-related motor protein purified from Drosophila embryos. J Biol Chem 269:22913–22916

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Enos AP, Morris NR (1990) Mutation of a gene that encodes a kinesin-like protein blocks nuclear division in A. nidulans. Cell 60:1019–1027

    Article  CAS  PubMed  Google Scholar 

  50. Hagan I, Yanagida M (1992) Kinesin-related cut7 protein associates with mitotic and meiotic spindles in fission yeast. Nature 356:74–76

    Article  CAS  PubMed  Google Scholar 

  51. Heck MM, Pereira A, Pesavento P, Yannoni Y, Spradling AC, Goldstein LS (1993) The kinesin-like protein KLP61F is essential for mitosis in Drosophila. J Cell Biol 123:665–679

    Article  CAS  PubMed  Google Scholar 

  52. Muretta JM, Behnke-Parks WM, Major J, Petersen KJ, Goulet A, Moores CA, Thomas DD, Rosenfeld SS (2013) Loop L5 assumes three distinct orientations during the ATPase cycle of the mitotic kinesin Eg5: a transient and time-resolved fluorescence study. J Biol Chem 288:34839–34849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Muretta JM, Jun Y, Gross SP, Major J, Thomas DD, Rosenfeld SS (2015) The structural kinetics of switch-1 and the neck linker explain the functions of kinesin-1 and Eg5. Proc Natl Acad Sci USA 112:E6606–E6613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Saunders WS, Hoyt MA (1992) Kinesin-related proteins required for structural integrity of the mitotic spindle. Cell 70:451–458

    Article  CAS  PubMed  Google Scholar 

  55. Gordon DM, Roof DM (1999) The kinesin-related protein Kip1p of Saccharomyces cerevisiae is bipolar. J Biol Chem 274:28779–28786

    Article  CAS  PubMed  Google Scholar 

  56. Kashina AS, Baskin RJ, Cole DG, Wedaman KP, Saxton WM, Scholey JM (1996) A bipolar kinesin. Nature 379:270–272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Scholey JE, Nithianantham S, Scholey JM, Al-Bassam J (2014) Structural basis for the assembly of the mitotic motor Kinesin-5 into bipolar tetramers. Elife 3:e02217

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Kapitein LC, Peterman EJ, Kwok BH, Kim JH, Kapoor TM, Schmidt CF (2005) The bipolar mitotic kinesin Eg5 moves on both microtubules that it crosslinks. Nature 435:114–118

    Article  CAS  PubMed  Google Scholar 

  59. van den Wildenberg SM, Tao L, Kapitein LC, Schmidt CF, Scholey JM, Peterman EJ (2008) The homotetrameric kinesin-5 KLP61F preferentially crosslinks microtubules into antiparallel orientations. Curr Biol 18:1860–1864

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Asraf H, Avunie-Masala R, Hershfinkel M, Gheber L (2015) Mitotic slippage and expression of survivin are linked to differential sensitivity of human cancer cell-lines to the kinesin-5 inhibitor monastrol. PLoS One 10:e0129255

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Blangy A, Lane HA, d’Herin P, Harper M, Kress M, Nigg EA (1995) Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell 83:1159–1169

    Article  CAS  PubMed  Google Scholar 

  62. Leizerman I, Avunie-Masala R, Elkabets M, Fich A, Gheber L (2004) Differential effects of monastrol in two human cell lines. Cell Mol Life Sci 61:2060–2070

    Article  CAS  PubMed  Google Scholar 

  63. FitzHarris G (2012) Anaphase B precedes anaphase A in the mouse egg. Curr Biol 22:437–444

    Article  CAS  PubMed  Google Scholar 

  64. Gerson-Gurwitz A, Movshovich N, Avunie R, Fridman V, Moyal K, Katz B, Hoyt MA, Gheber L (2009) Mid-anaphase arrest in S. cerevisiae cells eliminated for the function of Cin8 and dynein. Cell Mol Life Sci 66:301–313

    Article  CAS  PubMed  Google Scholar 

  65. Movshovich N, Fridman V, Gerson-Gurwitz A, Shumacher I, Gertsberg I, Fich A, Hoyt MA, Katz B, Gheber L (2008) Slk19-dependent mid-anaphase pause in kinesin-5-mutated cells. J Cell Sci 121:2529–2539

    Article  CAS  PubMed  Google Scholar 

  66. Saunders WS, Koshland D, Eshel D, Gibbons IR, Hoyt MA (1995) Saccharomyces cerevisiae kinesin- and dynein-related proteins required for anaphase chromosome segregation. J Cell Biol 128:617–624

    Article  CAS  PubMed  Google Scholar 

  67. Sharp DJ, McDonald KL, Brown HM, Matthies HJ, Walczak C, Vale RD, Mitchison TJ, Scholey JM (1999) The bipolar kinesin, KLP61F, cross-links microtubules within interpolar microtubule bundles of Drosophila embryonic mitotic spindles. J Cell Biol 144:125–138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Straight AF, Sedat JW, Murray AW (1998) Time-lapse microscopy reveals unique roles for kinesins during anaphase in budding yeast. J Cell Biol 143:687–694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Collins E, Mann BJ, Wadsworth P (2014) Eg5 restricts anaphase B spindle elongation in mammalian cells. Cytoskeleton (Hoboken) 71:136–144

    Article  CAS  Google Scholar 

  70. Saunders AM, Powers J, Strome S, Saxton WM (2007) Kinesin-5 acts as a brake in anaphase spindle elongation. Curr Biol 17:R453–R454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kwok BH, Yang JG, Kapoor TM (2004) The rate of bipolar spindle assembly depends on the microtubule-gliding velocity of the mitotic kinesin Eg5. Curr Biol 14:1783–1788

    Article  CAS  PubMed  Google Scholar 

  72. Nadar VC, Ketschek A, Myers KA, Gallo G, Baas PW (2008) Kinesin-5 is essential for growth-cone turning. Curr Biol 18:1972–1977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Baas PW, Matamoros AJ (2015) Inhibition of kinesin-5 improves regeneration of injured axons by a novel microtubule-based mechanism. Neural Regen Res 10:845–849

    Article  PubMed  PubMed Central  Google Scholar 

  74. Jakobs M, Franze K, Zemel A (2015) Force generation by molecular-motor-powered microtubule bundles; implications for neuronal polarization and growth. Front Cell Neurosci 9:441

    Article  PubMed  PubMed Central  Google Scholar 

  75. Kahn OI, Sharma V, Gonzalez-Billault C, Baas PW (2015) Effects of kinesin-5 inhibition on dendritic architecture and microtubule organization. Mol Biol Cell 26:66–77

    Article  PubMed  PubMed Central  Google Scholar 

  76. Myers KA, Baas PW (2007) Kinesin-5 regulates the growth of the axon by acting as a brake on its microtubule array. J Cell Biol 178:1081–1091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Nadar VC, Lin S, Baas PW (2012) Microtubule redistribution in growth cones elicited by focal inactivation of kinesin-5. J Neurosci 32:5783–5794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Chen Y, Hancock WO (2015) Kinesin-5 is a microtubule polymerase. Nat Commun 6:8160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Fridman V, Gerson-Gurwitz A, Shapira O, Movshovich N, Lakamper S, Schmidt CF, Gheber L (2013) Kinesin-5 Kip1 is a bi-directional motor that stabilizes microtubules and tracks their plus-ends in vivo. J Cell Sci 126:4147–4159

    Article  CAS  PubMed  Google Scholar 

  80. Fridman V, Gerson-Gurwitz A, Movshovich N, Kupiec M, Gheber L (2009) Midzone organization restricts interpolar microtubule plus-end dynamics during spindle elongation. EMBO Rep 10:387–393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Gardner MK, Bouck DC, Paliulis LV, Meehl JB, O’Toole ET, Haase J, Soubry A, Joglekar AP, Winey M, Salmon ED, Bloom K, Odde DJ (2008) Chromosome congression by Kinesin-5 motor-mediated disassembly of longer kinetochore microtubules. Cell 135:894–906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Rogers GC, Rogers SL, Sharp DJ (2005) Spindle microtubules in flux. J Cell Sci 118:1105–1116

    Article  CAS  PubMed  Google Scholar 

  83. Brust-Mascher I, Civelekoglu-Scholey G, Kwon M, Mogilner A, Scholey JM (2004) Model for anaphase B: role of three mitotic motors in a switch from poleward flux to spindle elongation. Proc Natl Acad Sci USA 101:15938–15943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Brust-Mascher I, Sommi P, Cheerambathur DK, Scholey JM (2009) Kinesin-5-dependent poleward flux and spindle length control in Drosophila embryo mitosis. Mol Biol Cell 20:1749–1762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Maddox PS, Bloom KS, Salmon ED (2000) The polarity and dynamics of microtubule assembly in the budding yeast Saccharomyces cerevisiae. Nat Cell Biol 2:36–41

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Mallavarapu A, Sawin K, Mitchison T (1999) A switch in microtubule dynamics at the onset of anaphase B in the mitotic spindle of Schizosaccharomyces pombe. Curr Biol 9:1423–1426

    Article  CAS  PubMed  Google Scholar 

  87. De Wulf P, McAinsh AD, Sorger PK (2003) Hierarchical assembly of the budding yeast kinetochore from multiple subcomplexes. Genes Dev 17:2902–2921

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Tytell JD, Sorger PK (2006) Analysis of kinesin motor function at budding yeast kinetochores. JCB 172:861–874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Wargacki MM, Tay JC, Muller EG, Asbury CL, Davis TN (2010) Kip3, the yeast kinesin-8, is required for clustering of kinetochores at metaphase. Cell Cycle 9:2581–2588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Cui H, Ghosh SK, Jayaram M (2009) The selfish yeast plasmid uses the nuclear motor Kip1p but not Cin8p for its localization and equal segregation. J Cell Biol 185:251–264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Prajapati HK, Rizvi SM, Rathore I, Ghosh SK (2017) Microtubule-associated proteins, Bik1 and Bim1, are required for faithful partitioning of the endogenous 2 micron plasmids in budding yeast. Mol Microbiol 103:1046–1064

    Article  CAS  PubMed  Google Scholar 

  92. Rizvi SMA, Prajapati HK, Ghosh SK (2017) The 2 micron plasmid: a selfish genetic element with an optimized survival strategy within Saccharomyces cerevisiae. Curr Genet 8:017–0719

    Google Scholar 

  93. Cochran JC (2015) Kinesin motor enzymology: chemistry, structure, and physics of nanoscale molecular machines. Biophys Rev 7:269–299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Cross RA (2016) Review: mechanochemistry of the kinesin-1 ATPase. Biopolymers 105:476–482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Friel CT, Howard J (2012) Coupling of kinesin ATP turnover to translocation and microtubule regulation: one engine, many machines. J Muscle Res Cell Motil 33:377–383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Goulet A, Moores C (2013) New insights into the mechanism of force generation by kinesin-5 molecular motors. Int Rev Cell Mol Biol 304:419–466

    Article  CAS  PubMed  Google Scholar 

  97. Waitzman JS, Rice SE (2014) Mechanism and regulation of kinesin-5, an essential motor for the mitotic spindle. Biol Cell 106:1–12

    Article  CAS  PubMed  Google Scholar 

  98. Endow SA, Waligora KW (1998) Determinants of kinesin motor polarity. Science 281:1200–1202

    Article  CAS  PubMed  Google Scholar 

  99. Goulet A, Behnke-Parks WM, Sindelar CV, Major J, Rosenfeld SS, Moores CA (2012) The structural basis of force generation by the mitotic motor kinesin-5. J Biol Chem 287:44654–44666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Henningsen U, Schliwa M (1997) Reversal in the direction of movement of a molecular motor. Nature 389:93–96

    Article  CAS  PubMed  Google Scholar 

  101. Higuchi H, Endow SA (2002) Directionality and processivity of molecular motors. Curr Opin Cell Biol 14:50–57

    Article  CAS  PubMed  Google Scholar 

  102. Schief WR, Howard J (2001) Conformational changes during kinesin motility. Curr Opin Cell Biol 13:19–28

    Article  CAS  PubMed  Google Scholar 

  103. Shastry S, Hancock WO (2011) Interhead tension determines processivity across diverse N-terminal kinesins. Proc Natl Acad Sci USA 108:16253–16258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Diefenbach RJ, Mackay JP, Armati PJ, Cunningham AL (1998) The C-terminal region of the stalk domain of ubiquitous human kinesin heavy chain contains the binding site for kinesin light chain. Biochemistry 37:16663–16670

    Article  CAS  PubMed  Google Scholar 

  105. Kanai Y, Dohmae N, Hirokawa N (2004) Kinesin transports RNA: isolation and characterization of an RNA-transporting granule. Neuron 43:513–525

    Article  CAS  PubMed  Google Scholar 

  106. Gerson-Gurwitz A, Thiede C, Movshovich N, Fridman V, Podolskaya M, Danieli T, Lakamper S, Klopfenstein DR, Schmidt CF, Gheber L (2011) Directionality of individual kinesin-5 Cin8 motors is modulated by loop 8, ionic strength and microtubule geometry. EMBO J 30:4942–4954

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Roostalu J, Hentrich C, Bieling P, Telley IA, Schiebel E, Surrey T (2011) Directional switching of the Kinesin cin8 through motor coupling. Science 332:94–99

    Article  CAS  PubMed  Google Scholar 

  108. Kasprzak AA, Hajdo L (2002) Directionality of kinesin motors. Acta Biochim Pol 49:813–821

    CAS  PubMed  Google Scholar 

  109. Kull FJ (2000) Motor proteins of the kinesin superfamily: structure and mechanism. Essays Biochem 35:61–73

    Article  CAS  PubMed  Google Scholar 

  110. Acar S, Carlson DB, Budamagunta MS, Yarov-Yarovoy V, Correia JJ, Ninonuevo MR, Jia W, Tao L, Leary JA, Voss JC, Evans JE, Scholey JM (2013) The bipolar assembly domain of the mitotic motor kinesin-5. Nat Commun 4:1343

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Hildebrandt ER, Gheber L, Kingsbury T, Hoyt MA (2006) Homotetrameric form of Cin8p, a Saccharomyces cerevisiae kinesin-5 motor, is essential for its in vivo function. J Biol Chem 281:26004–26013

    Article  CAS  PubMed  Google Scholar 

  112. Cahu J, Surrey T (2009) Motile microtubule crosslinkers require distinct dynamic properties for correct functioning during spindle organization in Xenopus egg extract. J Cell Sci 122:1295–1300

    Article  CAS  PubMed  Google Scholar 

  113. Tao L, Mogilner A, Civelekoglu-Scholey G, Wollman R, Evans J, Stahlberg H, Scholey JM (2006) A homotetrameric kinesin-5, KLP61F, bundles microtubules and antagonizes Ncd in motility assays. Curr Biol 16:2293–2302

    Article  CAS  PubMed  Google Scholar 

  114. Düselder A, Thiede C, Schmidt CF, Lakämper S (2012) Neck-linker length dependence of processive kinesin-5 motility. J Mol Biol 423:159–168

    Article  PubMed  CAS  Google Scholar 

  115. Gheber L, Kuo SC, Hoyt MA (1999) Motile properties of the kinesin-related Cin8p spindle motor extracted from Saccharomyces cerevisiae cells. J Biol Chem 274:9564–9572

    Article  CAS  PubMed  Google Scholar 

  116. Kapitein LC, Kwok BH, Weinger JS, Schmidt CF, Kapoor TM, Peterman EJ (2008) Microtubule cross-linking triggers the directional motility of kinesin-5. J Cell Biol 182:421–428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Lakämper S, Thiede C, Düselder A, Reiter S, Korneev MJ, Kapitein LC, Peterman EJ, Schmidt CF (2010) The effect of monastrol on the processive motility of a dimeric kinesin-5 head/kinesin-1 stalk chimera. J Mol Biol 399:1–8

    Article  PubMed  CAS  Google Scholar 

  118. 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 

  119. Edamatsu M (2014) Bidirectional motility of the fission yeast kinesin-5, Cut7. Biochem Biophys Res Commun 446:231–234

    Article  CAS  PubMed  Google Scholar 

  120. Shapira O, Goldstein A, Al-Bassam J, Gheber L (2017) A potential physiological role for bi-directional motility and motor clustering of mitotic kinesin-5 Cin8 in yeast mitosis. J Cell Sci 130:725–734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. 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 

  122. Fallesen T, Roostalu J, Duellberg C, Pruessner G, Surrey T (2017) Ensembles of bidirectional kinesin Cin8 produce additive forces in both directions of movement. Biophys J 113:2055–2067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Geng Y-Z, Li T, Ji Q, Yan S (2014) Simulation study of interactions between kinesin’s neck linker and motor domain. Cell Mol Bioeng 7:99–105

    Article  CAS  Google Scholar 

  124. Hwang W, Lang MJ, Karplus M (2008) Force generation in kinesin hinges on cover-neck bundle formation. Structure 16:62–71

    Article  CAS  PubMed  Google Scholar 

  125. Khalil AS, Appleyard DC, Labno AK, Georges A, Karplus M, Belcher AM, Hwang W, Lang MJ (2008) Kinesin’s cover-neck bundle folds forward to generate force. Proc Natl Acad Sci 105:19247–19252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Yi-Zhao G, Qing J, Shu-Xia L, Shi-Wei Y (2014) Initial conformation of kinesin’s neck linker. Chin Phys B 23:108701

    Article  CAS  Google Scholar 

  127. Edamatsu M (2016) Molecular properties of the N-terminal extension of the fission yeast kinesin-5, Cut7. Genet Mol Res 15:15017799

    Article  CAS  Google Scholar 

  128. Britto M, Goulet A, Rizvi S, von Loeffelholz O, Moores CA, Cross RA (2016) Schizosaccharomyces pombe kinesin-5 switches direction using a steric blocking mechanism. Proc Natl Acad Sci USA 113:E7483–E7489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. 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 

  130. Gigant B, Wang W, Dreier B, Jiang Q, Pecqueur L, Pluckthun 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 

  131. Kozielski F, Sack S, Marx A, Thormahlen M, Schonbrunn 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 

  132. Bell KM, Cha HK, Sindelar CV, Cochran JC (2017) The yeast kinesin-5 Cin8 interacts with the microtubule in a noncanonical manner. J Biol Chem 12:797662

    Google Scholar 

  133. Avunie-Masala R, Movshovich N, Nissenkorn Y, Gerson-Gurwitz A, Fridman V, Koivomagi M, Loog M, Hoyt MA, Zaritsky A, Gheber L (2011) Phospho-regulation of kinesin-5 during anaphase spindle elongation. J Cell Sci 124:873–878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Chee MK, Haase SB (2010) B-cyclin/CDKs regulate mitotic spindle assembly by phosphorylating kinesins-5 in budding yeast. PLoS Genet 6:e1000935

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Goldstein A, Siegler N, Goldman D, Judah H, Valk E, Koivomagi M, Loog M, Gheber L (2017) Three Cdk1 sites in the kinesin-5 Cin8 catalytic domain coordinate motor. Cell Mol Life Sci 28:017–2523

    Google Scholar 

  136. Shapira O, Gheber L (2016) Motile properties of the bi-directional kinesin-5 Cin8 are affected by phosphorylation in its motor domain. Sci Rep 6:25597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Hackney DD (1995) Highly processive microtubule-stimulated ATP hydrolysis by dimeric kinesin head domains. Nature 377:448–450

    Article  CAS  PubMed  Google Scholar 

  138. Kaan HY, Hackney DD, Kozielski F (2011) The structure of the kinesin-1 motor-tail complex reveals the mechanism of autoinhibition. Science 333:883–885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Weinger JS, Qiu M, Yang G, Kapoor TM (2011) A nonmotor microtubule binding site in kinesin-5 is required for filament crosslinking and sliding. Curr Biol 21:154–160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Goshima G, Vale RD (2005) Cell cycle-dependent dynamics and regulation of mitotic kinesins in Drosophila S2 cells. Mol Biol Cell 16:3896–3907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Sawin KE, Mitchison TJ (1995) Mutations in the kinesin-like protein Eg5 disrupting localization to the mitotic spindle. Proc Natl Acad Sci USA 92:4289–4293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Drummond DR, Hagan IM (1998) Mutations in the bimC box of Cut7 indicate divergence of regulation within the bimC family of kinesin related proteins. J Cell Sci 111(Pt 7):853–865

    CAS  PubMed  Google Scholar 

  143. Duselder A, Fridman V, Thiede C, Wiesbaum A, Goldstein A, Klopfenstein DR, Zaitseva O, Janson ME, Gheber L, Schmidt CF (2015) Deletion of the tail domain of the kinesin-5 Cin8 affects its directionality. J Biol Chem 19:620799

    Google Scholar 

  144. Saito N, Kaneko K (2017) Embedding dual function into molecular motors through collective motion. Sci Rep 7:44288

    Article  PubMed  PubMed Central  Google Scholar 

  145. Clift D, Schuh M (2015) A three-step MTOC fragmentation mechanism facilitates bipolar spindle assembly in mouse oocytes. Nat Commun 6:7217

    Article  PubMed  PubMed Central  Google Scholar 

  146. Sommi P, Cheerambathur D, Brust-Mascher I, Mogilner A (2011) Actomyosin-dependent cortical dynamics contributes to the prophase force-balance in the early Drosophila embryo. PLoS One 6:e18366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Courtheoux T, Gay G, Reyes C, Goldstone S, Gachet Y, Tournier S (2007) Dynein participates in chromosome segregation in fission yeast. Biol Cell 99:627–637

    Article  CAS  PubMed  Google Scholar 

  148. Li YY, Yeh E, Hays T, Bloom K (1993) Disruption of mitotic spindle orientation in a yeast dynein mutant. Proc Natl Acad Sci USA 90:10096–10100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Blackwell R, Edelmaier C, Sweezy-Schindler O, Lamson A, Gergely ZR, O’Toole E, Crapo A, Hough LE, McIntosh JR, Glaser MA, Betterton MD (2017) Physical determinants of bipolar mitotic spindle assembly and stability in fission yeast. Sci Adv 3:e1601603

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Adams AE, Pringle JR (1984) Relationship of actin and tubulin distribution to bud growth in wild-type and morphogenetic-mutant Saccharomyces cerevisiae. J Cell Biol 98:934–945

    Article  CAS  PubMed  Google Scholar 

  151. Allan VJ (2011) Cytoplasmic dynein. Biochem Soc Trans 39:1169–1178

    Article  CAS  PubMed  Google Scholar 

  152. Arnold K, Bordoli L, Kopp J, Schwede T (2006) The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics 22:195–201

    Article  CAS  PubMed  Google Scholar 

  153. Ferenz NP, Gable A, Wadsworth P (2010) Mitotic functions of kinesin-5. Semin Cell Dev Biol 21:255–259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. McCully EK, Robinow CF (1971) Mitosis in the fission yeast Schizosaccharomyces pombe: a comparative study with light and electron microscopy. J Cell Sci 9:475–507

    CAS  PubMed  Google Scholar 

  155. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in part by the Israel Science Foundation (ISF) (Grant 165/13 to L.G.), the National Science Foundation (NSF-1615991), United States—Israel Binational Science Foundation (BSF Grant BSF-2015851 to L.G. and J.A.-B.) and the National Institutes of Health (Grant NIH-R01-GM11283 to J.A.-B.). This manuscript has been deposited in PMC for release after 12 months.

Author information

Authors and Affiliations

  1. Department of Chemistry and Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, PO Box 653, 84105, Beer-Sheva, Israel

    Sudhir Kumar Singh, Himanshu Pandey & Larisa Gheber

  2. Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA, 95616, USA

    Jawdat Al-Bassam

Authors
  1. Sudhir Kumar Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Himanshu Pandey
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jawdat Al-Bassam
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Larisa Gheber
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Larisa Gheber.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Singh, S.K., Pandey, H., Al-Bassam, J. et al. Bidirectional motility of kinesin-5 motor proteins: structural determinants, cumulative functions and physiological roles. Cell. Mol. Life Sci. 75, 1757–1771 (2018). https://doi.org/10.1007/s00018-018-2754-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-018-2754-7

Keywords

Search

Navigation