Intrinsically disordered tubulin tails: complex tuners of microtubule functions?

Abstract

Microtubules are essential cellular polymers assembled from tubulin heterodimers. The tubulin dimer consists of a compact folded globular core and intrinsically disordered C-terminal tails. The tubulin tails form a lawn of densely grafted, negatively charged, flexible peptides on the exterior of the microtubule, potentially akin to brush polymers in the field of synthetic materials. These tails are hotspots for conserved, chemically complex posttranslational modifications that have the potential to act in a combinatorial fashion to regulate microtubule polymer dynamics and interactions with microtubule effectors, giving rise to a "tubulin code". In this review, I summarize our current knowledge of the enzymes that generate the astonishing tubulin chemical diversity observed in cells and describe recent advances in deciphering the roles of tubulin C-terminal tails and their posttranslational modifications in regulating the activity of molecular motors and microtubule associated proteins. Lastly, I outline the promises, challenges and potential pitfalls of deciphering the tubulin code.

Keywords: Brush polymer; Intrinsically disordered proteins; Microtubule; Molecular motors; Post-translational modification; Tubulin tyrosine ligase.

Figure 1. Structure of the αβ-tubulin dimer.

Sites of known posttranslational modifications are indicated by colored spheres (tyrosination, yellow; glutamylation, red; glycylation, cyan; acetylation, magenta; phosphorylation, grey).

Figure 2. Microtubules are decorated with posttranslational modifications inside and outside.

A. View of the microtubule exterior surface showing the C-terminal tails decorating the microtubule shaft. Posttranslational modifications are denoted by colored spheres (tyrosination, yellow; glutamylation, red; glycylation, cyan). B. View of the microtubule lumen. Acetylation at Lys40 is denoted by magenta spheres.

Figure 3. Tubulin C-terminal tails are variable and highly negatively charged.

Tubulin tail sequences from human α- and β-tubulin isoforms. Tubulin tail residues are in bold. Total net charge on the tubulin tails is indicated (including the C-terminal carboxylate).

Figure 4. Chemical structures of posttranslational modifications added to the disordered tubulin C-terminal tails.

A. Tyrosination B. Glutamylation C. Glycylation

Figure 5. TTL is the structural core of the TTL-like family of tubulin modification enzymes.

A Surface representation of TTL color-coded according to sequence conservation. B. Schematic domain representation of TTLL family members (residue numbers are for Mus Musculus sequences); tyrosine ligase shown in yellow; glutamylases, in red and glycylases, in cyan.