Key Points
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Microtubules are involved in various functions, which are mediated by complex interactions with a large range of microtubule-interacting proteins, such as motor proteins, microtubule stabilizers and destabilizers. The emerging role of post-translational modifications (PTMs) of tubulin sheds new light on the spatial and temporal control of microtubule functions.
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Microtubules undergo a wide array of reversible PTMs, including detyrosination, acetylation, Δ2-modification, polyglutamylation and polyglycylation.
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The PTMs predominate in more stable microtubule structures, that is, axons, cilia, flagella, centrioles and cytokinetic midbodies, but are in some cases also enriched on more dynamic microtubules, such as the mitotic spindle.
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Tubulin PTMs are responsible for altering the dynamics of microtubules, their interactions with motors and the action of severing proteins.
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Because of their many roles in regulating microtubule behaviour, microtubule PTMs are vital to a range of microtubule functions, including cell division, cell motility, cell signalling, neuronal development and brain function.
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Most of the enzymes that carry out the modifications, as well as those that reverse them, have been identified recently, enabling functional studies. After an initial rise of interest in tubulin PTMs in the 1980s and early 1990s, the field has only recently regained a strong interest in the scientific community.
Abstract
Half a century of biochemical and biophysical experiments has provided attractive models that may explain the diverse functions of microtubules within cells and organisms. However, the notion of functionally distinct microtubule types has not been explored with similar intensity, mostly because mechanisms for generating divergent microtubule species were not yet known. Cells generate distinct microtubule subtypes through expression of different tubulin isotypes and through post-translational modifications, such as detyrosination and further cleavage to Δ2-tubulin, acetylation, polyglutamylation and polyglycylation. The recent discovery of enzymes responsible for many tubulin post-translational modifications has enabled functional studies demonstrating that these post-translational modifications may regulate microtubule functions through an amazing range of mechanisms.
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Change history
01 March 2012
On page 776 of the above article, there was a mistake in figure 1a: the carboxy-terminal tail of α-tubulin should contain two Glu residues (instead of one) just before the terminal Tyr residue (that is, EEY rather than EY). This has been corrected online. We apologize for any confusion caused to readers.
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Acknowledgements
C.J. is supported by the Institut Curie, the Centre National de la Recherche Scientifique (CNRS) and the Institut National de la Santé et de la Recherche Médicale (INSERM), as well as by award 3140 of the Association pour la Recherche sur le Cancer (ARC), the French National Research Agency (ANR) awards 05-JCJC-0035 and 08-JCJC-0007, the Fondation pour la Recherche Médicale (FRM) research grant DEQ20081213977, the Human Frontier Science Program (HFSP) grant RGP 23/2008 and the European Molecular Biology Organization (EMBO) Young Investigator Program. J.C.B. is supported by Columbia University, USA, and The US National Institute of General Medical Sciences (NIGMS) grant R01 GM088660. We are very grateful to M. Steinmetz for help with figure 2b and for helpful comments and discussions and to L. Amos for allowing us to use a figure from reference 155 for the production of figure 2a. We further thank A. Fleury-Aubusson, M. M. Magiera, D. Needleman and T. Surrey for helpful discussions and critical reading of the manuscript.
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Supplementary information
Supplementary information S1 (box)
Discovery of enzymatic ligation of amino acids (PDF 77 kb)
Supplementary information S2 (box)
Reagents and experimental tools used in studying tubulin PTMs (PDF 180 kb)
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Glossary
- Centrioles
-
Barrel-shaped microtubule structures that generally assemble from nine triplet microtubules. A pair of centrioles surrounded by an amorphous mass constitutes the centrosome. Centrioles also serve as the basal body in ciliogenesis.
- Axonemes
-
Assemblies of microtubule doublets and singlets that form the core structures of cilia and flagella. The axoneme typically has a ring of nine outer microtubule doublets, which is assembled onto the basal body. Most motile cilia possess an extra central pair of microtubules.
- Mitotic spindle
-
A dynamic structure composed of microtubules and associated proteins that assembles around condensed chromosomes and exerts the forces that lead to their separation into the daughter cells during cell division.
- Midbody
-
A structure that connects the two daughter cells at the end of cell division, before cytokinetic abscission. It contains bundles of microtubules derived from the central region of the mitotic spindle, and other proteins that are important for cytokinesis.
- Kinesins
-
Motor proteins that move along microtubules (generally towards the plus end) by hydrolysing ATP. They have vital roles in most microtubule functions and constitute a diverse family, which also includes proteins with non-motile functions, such as microtubule depolymerization.
- Dyneins
-
Large motor protein complexes that move along microtubules towards the minus end by hydrolysing ATP to carry out intracellular transport and force generation. They are an integral part of the axoneme in motile cilia and flagella, generating their characteristic beat and also participating in intraflagellar transport.
- Carboxypeptidase
-
A protease that cleaves peptide bonds at the carboxyl terminus of peptide chains. It can be specific for a single amino acid, as is the case for the cytosolic carboxypeptidases described in this Review.
- Elongator protein complex
-
(ELP complex). A multisubunit histone acetyltransferase that acetylates histone H3 and is associated with nascent mRNAs in yeast. It has been implicated in α-tubulin acetylation.
- MYC-nick
-
A cytoplasmic cleavage product of MYC that is generated by calpain-dependent proteolysis of full-length MYC at Lys298.
- Axons
-
Filamentous projections that extrude from the cell body of neurons, transmit information away from the cell body via electrical impulses and are the site of axonal transport. There is normally one axon per neuron; other, smaller protrusions are dendrites.
- Blot-overlay assays
-
A method to identify specific protein–protein interactions. Target proteins are resolved on polyacrylamide gels and transferred onto nitrocellulose membranes, which are overlaid with a solution containing potential interacting proteins. Interacting proteins bound to the membrane are then visualized by antibody staining.
- CAP-Gly domain proteins
-
Regulators of microtubule dynamics that contain a ∼70-residue protein domain with several Gly residues and a hydrophobic cavity with a highly conserved GKNDG sequence that binds to the carboxy-terminal EEY or EEF sequence motifs of α-tubulin, end-binding proteins, and cytoplasmic linker protein 170 (CLIP170).
- Dynactin
-
A multisubunit protein complex that supports bidirectional intracellular transport by binding to dynein and Kinesin-2 and linking them to vesicle cargoes. It interacts with dynein via the CAP-Gly protein p150glued.
- Astral microtubules
-
Extend radially from the mitotic spindle towards the plasma membrane of the cell. They do not attach to chromosomes but play an essential part in orienting the mitotic spindle and the plane of cytokinesis.
- Kinetochore fibres
-
Generate the mechanical force for chromosome segregation and are composed of mitotic spindle microtubules that connect the poles of the spindle to each kinetochore.
- Growth cone
-
A dynamic structure at the tip of growing axons. In response to extracellular signals, it migrates and guides axons to their target areas, where they are remodelled into a synapse. The function of growth cones relies on highly dynamic actin and microtubule cytoskeletons.
- Purkinje cell
-
GABAergic (γ-aminobutyric acid-ergic) neurons located in the Purkinje layer of the cerebellum. Purkinje cells are some of the largest neurons in the brain; they are characterized by a highly differentiated dendritic tree and constitute the only output of the entire motor coordination in the cerebellum.
- Short hairpin RNA
-
(shRNA). Short RNA sequences that can be expressed in cells to silence gene expression. DNA sequences for shRNA templates are cloned into plasmids under the control of a U6 or an H1 promoter; the RNA forms a tight hairpin that is sufficient to silence the target gene.
- Primary cilia
-
Immotile cilia that are present in most cells of vertebrate organisms, in which they function in cell–cell signalling during development and also in mechanical sensing by some cell types.
- Intraflagellar transport
-
(IFT). The bidirectional transport of membrane-free particles within cilia and flagella. IFT particles move along the microtubules of the axoneme, driven by two motors: Kinesin-2 for anterograde transport; and cytoplasmic dynein 1b for retrograde transport.
- Basal bodies
-
A type of centriole that is inserted into the membrane at the base of a cilium or flagellum, where it serves as a nucleation site for the growth of the axoneme. Essential for the formation of cilia and flagella and for their anchoring at the cell membrane.
- Ciliopathies
-
Diseases that are caused by ciliary defects. Left-right asymmetry disorders, hydrocephalus and male sterility can result from the malfunction or absence of motile cilia. Diseases that are less obviously related to cilia, such as polycystic kidney disease, developmental disorders and cancer, result from the absence or malfunction of primary cilia and the consequent loss of their signalling functions.
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Janke, C., Chloë Bulinski, J. Post-translational regulation of the microtubule cytoskeleton: mechanisms and functions. Nat Rev Mol Cell Biol 12, 773–786 (2011). https://doi.org/10.1038/nrm3227
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DOI: https://doi.org/10.1038/nrm3227
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