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Growth, fluctuation and switching at microtubule plus ends

Nature Reviews Molecular Cell Biology volume 10, pages 569–574 (2009)Cite this article

Abstract

Recent experiments suggest that microtubules do not grow steadily but instead elongate at a rate that varies in time. We argue that this variation might arise from fluctuations in the length of a dynamic GTP–tubulin cap at the microtubule end. We propose that these fluctuations can lead to a switch in the dynamics of a microtubule end between growth and shrinkage, and provide insight into how the sensitivity of this switch can be changed by microtubule polymerases, such as XMAP215, and tensile forces, through the stabilization of initial contacts in the cap.

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Figure 1: Regulation of growth and shrinkage of microtubules.
Figure 2: Dynamic cap model.
Figure 3: Tubulin GTPase cycle.
Figure 4: Atomic force microscopy images of microtubule protofilaments.

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References

  1. Desai, A. & Mitchison, T. J. Microtubule polymerization dynamics. Annu. Rev. Cell Dev. Biol. 13, 83–117 (1997).

    CAS  PubMed  Google Scholar 

  2. Howard, J. & Hyman, A. A. Dynamics and mechanics of the microtubule plus end. Nature 422, 753–758 (2003).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Kirschner, M. & Mitchison, T. Beyond self-assembly: from microtubules to morphogenesis. Cell 45, 329–342 (1986).

    Article  CAS  PubMed  Google Scholar 

  5. Hayden, J. H., Bowser, S. S. & Rieder, C. L. Kinetochores capture astral microtubules during chromosome attachment to the mitotic spindle: direct visualization in live newt lung cells. J. Cell Biol. 111, 1039–1045 (1990).

    Article  CAS  PubMed  Google Scholar 

  6. Holy, T. E., Dogterom, M., Yurke, B. & Leibler, S. Assembly and positioning of microtubule asters in microfabricated chambers. Proc. Natl Acad. Sci. USA 94, 6228–6231 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rodionov, V. I. & Borisy, G. G. Self-centring activity of cytoplasm. Nature 386, 170–173 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Howard, J. Elastic and damping forces generated by confined arrays of dynamic microtubules. Phys. Biol. 3, 54–66 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Tolić-Nørrelykke, I. M. Push-me-pull-you: how microtubules organize the cell interior. Eur. Biophys. J. 37, 1271–1278 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Nogales, E., Wolf, S. G. & Downing, K. H. Structure of the αβ tubulin dimer by electron crystallography. Nature 391, 199–203 (1998); erratum 393, 191 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Hyman, A. A., Salser, S., Drechsel, D. N., Unwin, N. & Mitchison, T. J. Role of GTP hydrolysis in microtubule dynamics: information from a slowly hydrolyzable analogue, GMPCPP. Mol. Biol. Cell 3, 1155–1167 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Drechsel, D. N. & Kirschner, M. W. The minimum GTP cap required to stabilize microtubules. Curr. Biol. 4, 1053–1061 (1994); erratum 5, 215 (1995).

    Article  CAS  PubMed  Google Scholar 

  13. Sloboda, R. D., Rudolph, S. A., Rosenbaum, J. L. & Greengard, P. Cyclic AMP-dependent endogenous phosphorylation of a microtubule-associated protein. Proc. Natl Acad. Sci. USA 72, 177–181 (1975).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kinoshita, K., Habermann, B. & Hyman, A. A. XMAP215: a key component of the dynamic microtubule cytoskeleton. Trends Cell Biol. 12, 267–273 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Howard, J. & Hyman, A. A. Microtubule polymerases and depolymerases. Curr. Opin. Cell Biol. 19, 31–35 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Akhmanova, A. & Steinmetz, M. O. Tracking the ends: a dynamic protein network controls the fate of microtubule tips. Nature Rev. Mol. Cell Biol. 9, 309–322 (2008).

    Article  CAS  Google Scholar 

  17. Bieling, P. et al. Reconstitution of a microtubule plus-end tracking system in vitro. Nature 450, 1100–1105 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Bieling, P. et al. CLIP-170 tracks growing microtubule ends by dynamically recognizing composite EB1/tubulin-binding sites. J. Cell Biol. 183, 1223–1233 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. des Georges, A. et al. Mal3, the Schizosaccharomyces pombe homolog of EB1, changes the microtubule lattice. Nature Struct. Mol. Biol. 15, 1102–1108 (2008).

    Article  CAS  Google Scholar 

  20. Vitre, B. et al. EB1 regulates microtubule dynamics and tubulin sheet closure in vitro. Nature Cell Biol. 10, 415–421 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Komarova, Y. et al. Mammalian end binding proteins control persistent microtubule growth. J. Cell Biol. 184, 691–706 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Grishchuk, E. L., Molodtsov, M. I., Ataullakhanov, F. I. & McIntosh, J. R. Force production by disassembling microtubules. Nature 438, 384–388 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Kerssemakers, J. W. et al. Assembly dynamics of microtubules at molecular resolution. Nature 442, 709–712 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Schek, H. T., Gardner, M. K., Cheng, J., Odde, D. J. & Hunt, A. J. Microtubule assembly dynamics at the nanoscale. Curr. Biol. 17, 1445–1455 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Asbury, C. L., Gestaut, D. R., Powers, A. F., Franck, A. D. & Davis, T. N. The Dam1 kinetochore complex harnesses microtubule dynamics to produce force and movement. Proc. Natl Acad. Sci. USA 103, 9873–9878 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hill, T. L. & Kirschner, M. W. Bioenergetics and kinetics of microtubule and actin filament assembly–disassembly. Int. Rev. Cytol. 78, 1–125 (1982).

    CAS  PubMed  Google Scholar 

  27. VanBuren, V., Cassimeris, L. & Odde, D. J. Mechanochemical model of microtubule structure and self-assembly kinetics. Biophys. J. 89, 2911–2926 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mozziconacci, J., Sandblad, L., Wachsmuth, M., Brunner, D. & Karsenti, E. Tubulin dimers oligomerize before their incorporation into microtubules. PLoS ONE 3, e3821 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Chrétien, D., Fuller, S. D. & Karsenti, E. Structure of growing microtubule ends: two-dimensional sheets close into tubes at variable rates. J. Cell Biol. 129, 1311–1328 (1995).

    Article  PubMed  Google Scholar 

  30. Howard, J. Mechanics of Motor Proteins and the Cytoskeleton (Sinauer Associates, Sunderland, Massachusetts, 2001).

    Google Scholar 

  31. Müller-Reichert, T., Chrétien, D., Severin, F. & Hyman, A. A. Structural changes at microtubule ends accompanying GTP hydrolysis: information from a slowly hydrolyzable analogue of GTP, guanylyl (α,β) methylenediphosphonate. Proc. Natl Acad. Sci. USA 95, 3661–3666 (1998).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Wang, H. W. & Nogales, E. Nucleotide-dependent bending flexibility of tubulin regulates microtubule assembly. Nature 435, 911–915 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Elie-Caille, C. et al. Straight GDP–tubulin protofilaments form in the presence of taxol. Curr. Biol. 17, 1765–1770 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Mandelkow, E. M., Mandelkow, E. & Milligan, R. A. Microtubule dynamics and microtubule caps: a time-resolved cryo-electron microscopy study. J. Cell Biol. 114, 977–991 (1991).

    Article  CAS  PubMed  Google Scholar 

  35. Ravelli, R. B. et al. Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain. Nature 428, 198–202 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Rice, L. M., Montabana, E. A. & Agard, D. A. The lattice as allosteric effector: structural studies of αβ- and γ-tubulin clarify the role of GTP in microtubule assembly. Proc. Natl Acad. Sci. USA 105, 5378–5383 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang, H. W. & Nogales, E. Nucleotide-dependent bending flexibility of tubulin regulates microtubule assembly. Nature 435, 911–915 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nogales, E., Whittaker, M., Milligan, R. A. & Downing, K. H. High-resolution model of the microtubule. Cell 96, 79–88 (1999).

    Article  CAS  PubMed  Google Scholar 

  39. Mickey, B. & Howard, J. Rigidity of microtubules is increased by stabilizing agents. J. Cell Biol. 130, 909–917 (1995).

    Article  CAS  PubMed  Google Scholar 

  40. Gard, D. L. & Kirschner, M. W. A microtubule-associated protein from Xenopus eggs that specifically promotes assembly at the plus-end. J. Cell Biol. 105, 2203–2215 (1987).

    Article  CAS  PubMed  Google Scholar 

  41. Tournebize, R. et al. Control of microtubule dynamics by the antagonistic activities of XMAP215 and XKCM1 in Xenopus egg extracts. Nature Cell Biol. 2, 13–19 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Cassimeris, L., Gard, D., Tran, P. T. & Erickson, H. P. XMAP215 is a long thin molecule that does not increase microtubule stiffness. J. Cell Sci. 114, 3025–3033 (2001).

    CAS  PubMed  Google Scholar 

  43. Al-Bassam, J., Larsen, N. A., Hyman, A. A. & Harrison, S. C. Crystal structure of a TOG domain: conserved features of XMAP215/Dis1-family TOG domains and implications for tubulin binding. Structure 15, 355–362 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Slep, K. C. & Vale, R. D. Structural basis of microtubule plus end tracking by XMAP215, CLIP-170, and EB1. Mol. Cell 27, 976–991 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Brouhard, G. J. et al. XMAP215 is a processive microtubule polymerase. Cell 132, 79–88 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Gard, D. L. & Kirschner, M. W. Microtubule assembly in cytoplasmic extracts of Xenopus oocytes and eggs. J. Cell Biol. 105, 2191–2201 (1987).

    Article  CAS  PubMed  Google Scholar 

  47. Arnal, I. & Wade, R. H. How does taxol stabilize microtubules? Curr. Biol. 5, 900–908 (1995).

    Article  CAS  PubMed  Google Scholar 

  48. Tyson, J. J., Chen, K. C. & Novak, B. Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell. Curr. Opin. Cell Biol. 15, 221–231 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Alon, U. An Introduction to Systems Biology (Chapman & Hall/CRC, Boca Raton, Florida, 2007).

    Google Scholar 

  50. Ferrell, J. E. & Xiong, W. Bistability in cell signaling: how to make continuous processes discontinuous, and reversible processes irreversible. Chaos 11, 227–236 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Franck, A. D. et al. Tension applied through the Dam1 complex promotes microtubule elongation providing a direct mechanism for length control in mitosis. Nature Cell Biol. 9, 832–837 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. McIntosh, J. R. et al. Fibrils connect microtubule tips with kinetochores: a mechanism to couple tubulin dynamics to chromosome motion. Cell 135, 322–333 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chretien, D., Fuller, S. D. & Karsenti, E. Structure of growing microtubule ends: two-dimensional sheets close into tubes at variable rates. J. Cell Biol. 129, 1311–1328 (1995).

    Article  CAS  PubMed  Google Scholar 

  54. Sandblad, L. et al. The Schizosaccharomyces pombe EB1 homolog Mal3p binds and stabilizes the microtubule lattice seam. Cell 127, 1415–1424 (2006).

    CAS  PubMed  Google Scholar 

  55. Dimitrov, A. et al. Detection of GTP-tubulin conformation in vivo reveals a role for GTP remnants in microtubule rescues. Science 322, 1353–1356 (2008).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank G. Brouhard, J. Stear, H. Erickson, V. Varga and M. Zanic for their comments on the manuscript, as well as M. Gardner, A. Hunt and D. Odde for figure 2.

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  1. Jonathon Howard and Anthony A. Hyman are at the Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany. howard@mpi-cbg.de; hyman@mpi-cbg.de,

    Jonathon Howard & Anthony A. Hyman

  2. hyman@mpi-cbg.de,

    Jonathon Howard & Anthony A. Hyman

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Howard, J., Hyman, A. Growth, fluctuation and switching at microtubule plus ends. Nat Rev Mol Cell Biol 10, 569–574 (2009). https://doi.org/10.1038/nrm2713

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