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Microtubule dynamics: an interplay of biochemistry and mechanics

Nature Reviews Molecular Cell Biology volume 19, pages 451–463 (2018)Cite this article

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Abstract

Microtubules are dynamic polymers of αβ-tubulin that are essential for intracellular organization, organelle trafficking and chromosome segregation. Microtubule growth and shrinkage occur via addition and loss of αβ-tubulin subunits, which are biochemical processes. Dynamic microtubules can also engage in mechanical processes, such as exerting forces by pushing or pulling against a load. Recent advances at the intersection of biochemistry and mechanics have revealed the existence of multiple conformations of αβ-tubulin subunits and their central role in dictating the mechanisms of microtubule dynamics and force generation. It has become apparent that microtubule-associated proteins (MAPs) selectively target specific tubulin conformations to regulate microtubule dynamics, and mechanical forces can also influence microtubule dynamics by altering the balance of tubulin conformations. Importantly, the conformational states of tubulin dimers are likely to be coupled throughout the lattice: the conformation of one dimer can influence the conformation of its nearest neighbours, and this effect can propagate over longer distances. This coupling provides a long-range mechanism by which MAPs and forces can modulate microtubule growth and shrinkage. These findings provide evidence that the interplay between biochemistry and mechanics is essential for the cellular functions of microtubules.

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Fig. 1: Tubulin biochemistry, conformation and mechanics.
Fig. 2: Regulatory proteins and the tubulin conformation cycle.
Fig. 3: Barriers to spontaneous and templated nucleation.
Fig. 4: Mechanical coupling in the microtubule lattice.

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Acknowledgements

The authors thank S. Chaaban for his masterful work in rendering the microtubule end in Box 1. The authors thank members of the Brouhard and Rice laboratories for helpful discussions and feedback on the manuscript. Work in G.J.B.’s laboratory is supported by the Canadian Institutes of Health Research (PJT-148702 and MOP-137055), the Natural Sciences and Engineering Research Council of Canada (RGPIN-2014-03791), the Fonds de recherche du Québec — Nature et technologies (FRQ-NT 191128), the Canadian Foundation for Innovation and McGill University. L.M.R. is the Thomas O. Hicks Scholar in Medical Research; work in his laboratory is supported by the National Institutes of Health (R01-GM098543), the National Science Foundation (MCB-1615938) and the Robert A. Welch Foundation (I-1908).

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Nature Reviews Molecular Cell Biology thanks E. Nogales and the other anonymous reviewer(s) for their contribution to the peer review of this work

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  1. Department of Biology, McGill University, Montréal, Quebec, Canada

    Gary J. Brouhard

  2. Department of Biophysics, University of Texas Southwestern, Dallas, TX, USA

    Luke M. Rice

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Glossary

End-binding (EB) proteins

A family of evolutionarily conserved proteins that autonomously track the growing microtubule end. EB proteins regulate microtubule dynamics and are also responsible for recruiting the majority of other plus-end tracking proteins to the growing microtubule end.

Microtubule polymerases

Regulatory factors that promote microtubule elongation, typically by making microtubules grow more quickly.

Microtubule depolymerases

Regulatory factors that promote microtubule depolymerization. Well-studied microtubule depolymerases include the mitotic centromere-associated kinesin (MCAK)–kinesin 13 and the Kip3–kinesin 8 families.

Kinesins

A large family of microtubule-associated proteins that use the energy from ATP hydrolysis to walk on microtubules and/or regulate their polymerization dynamics.

Plus end

The end of the microtubule that is crowned by β-tubulin subunits. This more dynamic end of the polymer typically grows from the centre of the cell towards the periphery.

Minus end

The end of the microtubule that is crowned by α-tubulin subunits. This less dynamic end of the polymer is typically capped or anchored in a microtubule-organizing structure such as the centrosome.

Interpolation (morphing)

A computational procedure that creates a series of structural intermediates between two known conformations of a molecule. Conformations generated by morphing provide a useful way to visualize intermediate steps along a conformational change but do not always capture the actual pathway for the conformational change.

Strain energy

Describes internal energy stored by a molecule when that molecule is held in an otherwise unfavourable conformation.

Compressive stress

Strain energy resulting from forces that push against the growing microtubule end.

Tensile stress

Strain energy resulting from forces that pull on the growing or shrinking microtubule end.

Optical tweezers

Device in which radiation pressure from a laser beam focused by a microscope objective is used to trap a small bead or other object. Optical tweezers provide a sensitive way to measure both the position of the trapped object and the forces experienced by the trapped object.

XMAP215 family

The best-studied family of microtubule polymerases. Polymerases in this family, which includes vertebrate XMAP215 and yeast Stu2, are the major factors that promote fast microtubule growth in cells, and their activity is important for proper formation of the mitotic spindle.

Free energy

A thermodynamic quantity that describes the amount of energy that can do work in a given system. The change in free energy associated with a chemical reaction provides the amount of work that is released by that reaction or that must be inputted to drive that reaction.

Baculovirus

A virus that infects invertebrate cells, engineered versions of which are used to direct the expression of heterologous proteins in insect cells.

Allosteric effect

Describes a phenomenon in which the enzymatic or binding activity of one region of a protein can be influenced by binding events at other regions.

Kinesin 13

Kinesin family proteins that act as microtubule depolymerases. These kinesins use ATP hydrolysis to induce outward curvature in protofilaments, triggering catastrophes. An example member of this family is mitotic centromere-associated kinesin (MCAK).

Kinesin 8

Family of kinesins that combines the motility of conventional kinesins with depolymerase activity. Because of this unique combination, some members of the family have been shown to depolymerize microtubules in a length-dependent manner. A well-studied member of the family is yeast kinesin-like protein Kip3.

Rescue factors

Regulatory factors that increase the likelihood of microtubule rescue. The best-studied rescue factors belong to the CLASP family.

TPX2

A spindle assembly factor that functions in the Ran–GTP pathway. TPX2 is released from importins in the vicinity of chromosomes, where it stimulates microtubule nucleation and interacts with motor proteins.

Microtubule nucleation

The process of forming a microtubule de novo (from unpolymerized αβ-tubulin subunits) or on a template such as the γ-tubulin ring complex or a severed microtubule end.

γ-tubulin ring complex

(γ-TuRC). A conical oligomer of γ-tubulins and γ-ring complex proteins (GCPs) that creates a template for microtubule nucleation.

Chromatin-mediated microtubule nucleation pathway

A pathway for microtubule nucleation wherein factors that promote nucleation are selectively activated in the vicinity of chromatin.

Branching nucleation

A microtubule-dependent microtubule nucleation pathway wherein new microtubules are nucleated from the sides of existing ones.

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Brouhard, G.J., Rice, L.M. Microtubule dynamics: an interplay of biochemistry and mechanics. Nat Rev Mol Cell Biol 19, 451–463 (2018). https://doi.org/10.1038/s41580-018-0009-y

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