Tubulin modifications and their cellular functions

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All microtubules are built from a basic α/β-tubulin building block, yet subpopulations of microtubules can be differentially marked by a number of post-translational modifications. These modifications, conserved throughout evolution, are thought to act individually or in combination to control specific microtubule-based functions, analogous to how histone modifications regulate chromatin functions. Here we review recent studies demonstrating that tubulin modifications influence microtubule-associated proteins such as severing proteins, plus-end tracking proteins, and molecular motors. In this way, tubulin modifications play an important role in regulating microtubule properties, such as stability and structure, as well as microtubule-based functions, such as ciliary beating, cell division, and intracellular trafficking.

Introduction

Microtubules are polar cytoskeletal filaments assembled from head-to-tail and lateral associations of α/β-tubulin heterodimers. Most microtubules occur as single tubes and form cellular structures such as the mitotic spindle and the interphase network (Figure 1). A subset of microtubules exist as fused structures where a complete microtubule (A tubule) is fused with one or two incomplete tubules (B and C tubules) to comprise ciliary axonemes (doublet microtubules) or centrioles and basal bodies (triplet microtubules) (Figure 1). How the basic α/β-tubulin building block is used to generate a variety of microtubule structures with organelle-specific properties and functions is not clear. One hypothesis that has gained experimental support recently is that post-translational modifications (PTMs) of the tubulin building block generate functional diversity of microtubules. These modifications may act individually and/or in a combinatorial fashion to recruit specific protein complexes and thus regulate organelle-specific properties of microtubules.

Many tubulin PTMs have been known for decades – detyrosination and the related Δ2 modification, glutamylation, glycylation, acetylation, phosphorylation, and palmitoylation (Figure 2) (for reviews, see [1, 2]). Yet their functional roles in different microtubule structures are just beginning to be discovered. Most PTMs occur on microtubules rather than on unpolymerized tubulin and it has long been known that stable microtubules, as compared to dynamic microtubules, accumulate more modifications. The PTMs are postulated to play a role in specific functions of stable microtubules as differences in tubulin PTM patterns can be seen between stable microtubules. For example, in axonemes, although all microtubules are highly stable, the A tubule of the doublet microtubules and the central singlet microtubules are mostly unmodified, whereas the B tubule is highly detyrosinated, polyglycylated, and polyglutamylated (Figure 1). This review will focus on the four best-studied PTMs of tubulin, with a particular focus on recent studies indicating specific functional roles for these modifications in regulating microtubule-based functions in vivo.

Section snippets

Detyrosination/tyrosination

Detyrosination involves the removal of the gene-encoded C-terminal tyrosine of α-tubulin in microtubule polymers by an unidentified carboxypeptidase (Figure 2) [1, 2]. A novel family of cytosolic carboxypeptidases was recently identified whose founding member, Nna1/CCP1, shares some characteristics with the known properties of tubulin carboxypeptidase [3, 4]. The reverse tyrosination reaction, or addition of a tyrosine residue to the now C-terminal glutamate residue of α-tubulin, occurs on

Polymodifications—glutamylation and glycylation

Glutamylation and glycylation involve the addition of variable numbers of glutamate or glycine residues, respectively, onto glutamate residues in the C-terminal tails (CTTs) of both α- and β-tubulin (Figure 2) [1, 2]. Glycylation is mainly limited to tubulin incorporated into axonemes (cilia and flagella) whereas glutamylation is prevalent in neuronal cells, centrioles, axonemes, and the mitotic spindle. Both modifications have been found on the same tubulin CTT and there is cross-talk between

Acetylation

Acetylation is unique among the known tubulin modifications in that it occurs on lysine 40 of α-tubulin which is postulated to reside on the luminal face of microtubules (Figure 2). It is unclear how the enzymes that carry out acetylation/deacetylation would have access to this site. It is also unclear how this luminal modification could influence microtubule-based functions that occur on the cytoplasmic face of the microtubule. The acetylation enzyme has not been identified, but two enzymes

Concluding remarks

Although PTMs of tubulin subunits within microtubule structures have been known for many years, the cellular functions of the PTMs have only recently begun to be revealed. So far, tubulin PTMs have been shown to affect primarily two microtubule-based properties. First, tubulin PTMs influence the stability and/or structure of microtubule assemblies. Whether this is a direct effect of tubulin modification on microtubule structure or indirectly because of regulation of microtubule-associated

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We apologize to those authors whose important work we have not cited because of restrictions in number of references and emphasis on publications within the past few years. We thank J. Gaertig and members of the Verhey lab for stimulating discussions and reading the manuscript. Work in the author's laboratory is supported in part by a grant from the National Institutes of Health (GM070862).

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