Microtubule dynamics and their control are essential for the normal function and division of all eukaryotic cells. This plethora of functions is, in large part, supported by dynamic microtubule tips, which can bind to various intracellular targets, generate mechanical forces and couple with actin microfilaments. Here, we review progress in the understanding of microtubule assembly and dynamics, focusing on new information about the structure of microtubule tips. First, we discuss evidence for the widely accepted GTP cap model of microtubule dynamics. Next, we address microtubule dynamic instability in the context of structural information about assembly intermediates at microtubule tips. Three currently discussed models of microtubule assembly and dynamics are reviewed. These are considered in the context of established facts and recent data, which suggest that some long-held views must be re-evaluated. Finally, we review structural observations about the tips of microtubules in cells and describe their implications for understanding the mechanisms of microtubule regulation by associated proteins, by mechanical forces and by microtubule-targeting drugs, prominently including cancer chemotherapeutics.
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The authors thank V. Alexandrova for critical reading of the manuscript and I. Lopanskaia for assistance with the figures. This work was partly supported by National Institutes of Health (NIH) grant GM033787 to J.R.M. Work on microtubule control by regulatory proteins was supported by Russian Foundation for Basic Research grant # 20-34-70159 and work on microtubule control by small-molecule inhibitors was supported by Russian Science Foundation grant # 21-74-20035 to N.B.G.
The authors declare that there is no conflict of interest.
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GTP-bound Ran (a member of the Ras superfamily, thus serving as a regulator of biological processes) that stimulates microtubule polymerization by activating several relevant proteins. During mitosis, the concentration of this complex is highest in the vicinity of chromosomes because a chromatin-localized nucleotide exchange factor facilitates conversion of freely diffusing Ran-GDP and GTP into Ran-GTP and GDP.
Conserved actin polymerases.
- Microtubule organizing centre
A cellular structure that nucleates microtubule polymerization in cells.
- Focal adhesions
Large protein assemblies that mechanically link the extracellular matrix to cytoplasmic bundles of actin.
A small molecule, derived from bark of the Pacific Yew tree Taxus brevifolia, which binds to microtubules and stabilizes them against depolymerization.
A small molecule that binds soluble tubulin and prevents its polymerization. Nocodazole therefore works as a microtubule-destabilizing agent.
Thin, membrane-coated, actin-rich protrusions of the cell surface.
- Immunological synapse
A junction between a T cell and an antigen-presenting cell.
- Microtubule cross-linkers
Proteins that connect two or more microtubules into a bundle.
A small-molecule microtubule-destabilizing agent derived from the African plant Combretum caffrum.
A slowly hydrolysable analogue of GTP in which the α-phosphates and β-phosphates are connected via a methylene link.
A small molecule derived from the plant Colchicum autumnale. It binds tubulin and works as a microtubule-destabilizing agent.
- Microtubule-associated proteins
A heterogeneous group of proteins that bind to microtubules. The group includes motor enzymes, some microtubule dynamics regulators, microtubule cross-linkers and so on.
A structure comprising the core of a eukaryotic cilium or flagellum. In primary (non-motile) cilia, it consists of nine microtubule doublets arranged in a cylinder. Motile cilia and flagella additionally have a pair of microtubules in the centre of the cylinder. Microtubules within the axoneme are bridged by multiple cross-linking proteins, including dynein motor proteins, which enable sliding of adjacent microtubule doublets to produce a beating motion.
- TOG domain-containing proteins
Microtubule-associated proteins that contain from two to five TOG (Tumour Overexpressed Gene) domains. These are tubulin-binding domains that can affect microtubule dynamics.
A small molecule, derived from the myxobacterium Sorangium cellulosum, which acts as a microtubule-stabilizing agent.
Large protein assemblies that form at a chromosome’s centromere. They are responsible for microtubule capture in mitosis.
- Microtubule flux
A cellular process in which a microtubule moves along its axis towards its minus end while tubulin subunits are added at its plus end and removed from its minus end. The microtubule moves, but both its ends and its centre of mass are stationary.
- Anaphase B
The second part of anaphase. During this stage of cell division, the mitotic spindle elongates through the growth and sliding apart of antiparallel, interpolar microtubules.
- Growth cones
Motile, actin-rich cellular specializations at the tips of neuronal extensions, such as axons and dendrites. Their motility draws the tips of a developing neuronal branch and enables the formation of neural connections.
A collective name for several microtubule-inhibiting peptides, derived from a mollusc from the Indian Ocean, Dolabella auricularia. The peptides bind tubulin and promote the formation of curved protofilament-like structure that commonly assemble into rings.
- Peloruside A
A small-molecule microtubule-stabilizing agent isolated from the New Zealand marine sponge Mycale hentscheli.
A small-molecule microtubule-stabilizing agent isolated from the marine sponge Cacospongia mycofijiensis.
- Vinca-domain ligands
Small molecules that destabilize microtubule assembly through binding to the same site on tubulin as vinblastine, an alkaloid derived from the Madagascar periwinkle plant Vinca rosea.
A small-molecule microtubule-destabilizing agent. It is a synthetic analogue of a polyether macrolide derived from the marine sponge Halichondria okadai.
A small-molecule microtubule-destabilizing agent derived from the plant Maytenus ovatus.
A small-molecule microtubule-destabilizing agent derived from the bacterium Streptomyces prunicolor.
- ‘Brownian ratchet’ mechanism
Any process in which directed motion of a small particle is achieved through ‘rectification’ of thermal fluctuations, fuelled by some external energy source, such as the growth of a polymer.
- Atomic force microscopy
A high-resolution, non-optical imaging method in which structural information about the sample is collected by raster-scanning a very thin, cylindrical probe with a sharp tip over a sample’s surface, using an optical feedback loop to adjust the parameters needed for imaging.
- Interferometric scattering microscopy
A sensitive method for optical microscopy in which contrast is achieved through interference of light scattered by the imaged particle with a reference wave that is partially reflected by the microscope slide or coverslip.
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Gudimchuk, N.B., McIntosh, J.R. Regulation of microtubule dynamics, mechanics and function through the growing tip. Nat Rev Mol Cell Biol 22, 777–795 (2021). https://doi.org/10.1038/s41580-021-00399-x
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