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Microtubules: 50 years on from the discovery of tubulin

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Abstract

Next year will be the 50th anniversary of the discovery of tubulin. To celebrate this discovery, six leaders in the field of microtubule research reflect on key findings and technological breakthroughs over the past five decades, discuss implications for therapeutic applications and provide their thoughts on what questions need to be addressed in the near future.

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Authors and Affiliations

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Correspondence to Gary Borisy, Rebecca Heald, Jonathon Howard, Carsten Janke, Andrea Musacchio or Eva Nogales.

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The authors declare no competing financial interests.

Glossary

Axonemes

Microtubule-based superstructures that run along the lengths of cilia and flagella. They typically contains two central microtubules surrounded by nine microtubule doublets.

Density maps

Distribution of mass corresponding to a macromolecule obtained by structural biology methods such as X-ray crystallography or cryoelectron microscopy.

Detyrosination–tyrosination cycle

A post-translational modification of α-tubulin, consisting of the enzymatic removal of the gene-encoded, carboxy-terminal Tyr residue (by enzymes yet unknown) and its enzymatic re-ligation by tubulin Tyr ligase.

Dynamic instability

A property of microtubules discovered in 1984 by Tim Mitchison and Mark Kirschner (then at the University of California San Francisco, USA), by which individual microtubules switch stochastically between phases of growth and shrinking, powered by GTP hydrolysis that closely follows incorporation of a tubulin dimer into a growing microtubule end.

Dynein and dynactin

Dynein is a complex, multi-subunit microtubule minus-end-directed motor. Studies in vitro suggest that its processive movement on microtubules may require dynactin, which is a very large multi-subunit assembly, as well as additional adaptor subunits.

GTP cap

A GTP–tubulin-rich structure at the growing tip of a microtubule, created by the binding of GTP-bound tubulin subunits from solution onto the microtubule end.

End-binding proteins

Proteins that bind with higher affinity to a region at the dynamic, growing end of a microtubule.

Fluorescent speckle microscopy

A live-imaging technique in which a low number of randomly incorporated labelled self-assembling subunits generate fluorescence intensity patterns that appear as distinct puncta, called speckles, that serve as fiduciary markers so that motion and turnover of the polymer can be visualized.

Kinesin

A family of small ATPases, distantly related to myosins and G proteins, that bind specifically to microtubules and undergo conformational changes upon ATP binding, hydrolysis and product (ADP and inorganic phosphate) release. The conformational changes can be used to drive directed motion, to generate force and to alter the growth or depolymerization of microtubules.

Kinetochore

A large protein assembly of nearly 100 proteins that links centromeric DNA to spindle microtubules, thereby coupling forces generated by microtubule dynamics to power chromosome movement during mitosis and meiosis.

Lattice accommodation theory

A geometrical model that explains how tubulin contacts can be maintained in microtubules with different protofilaments by skewing of the protofilaments with respect to the microtubule axis.

Optical or magnetic tweezers

Optical tweezers, also known as optical traps, are instruments that use a focused laser beam to generate forces on micrometre-scale objects. Magnetic tweezers are instruments that can generate forces or torque. Both instruments can operate in biologically meaningful force ranges, typically piconewtons, and are therefore ideally suited to study the interactions of microtubules with motors and microtubule-associated proteins.

Peptide antibodies

Antibodies raised against synthetic short peptides representing an epitope of a protein. If they are generated for a peptide mimicking a specific post-translational modification, the antibodies can be used to determine the state of this modification at the native protein.

Search-and-capture model

Proposed by Mitchison and Kirschner in 1886, this model builds on an intrinsic property of microtubules named dynamic instability. The search-and-capture model proposed that this property allows the dynamic ends of microtubules to explore space randomly, until their capture by defined binding targets (for example, kinetochores) endowed with the ability to suppress instability, which would therefore selectively stabilize on-target microtubules. Many aspects of this model have since been confirmed, including the strong stabilization of microtubules after kinetochore binding.

Total internal reflection fluorescence microscopy

(TIRF). An optical technique that exploits the 'trapping' of light within high-refractive-index structures such as optical fibres and even 'fluorescent' signs such as those sometimes used to advertise menus in cafes or restaurants, in which writing on the glass surface allows the light to leak out.

Tubulin code

Describes the process of generating specialized microtubules by directly changing the tubulin building blocks, either by the incorporation of specific tubulin isotypes (a set of gene products of α- and β-tubulins) into the lattice, or by the addition of specific post-translational modifications to tubulin.

Vinca alkaloids

A set of natural or semi-synthetic alkaloid agents derived from vinca plants, which have the capacity to inhibit microtubule assembly and are therefore used in cancer therapy.

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Borisy, G., Heald, R., Howard, J. et al. Microtubules: 50 years on from the discovery of tubulin. Nat Rev Mol Cell Biol 17, 322–328 (2016). https://doi.org/10.1038/nrm.2016.45

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