The chemical complexity of cellular microtubules: Tubulin post‐translational modification enzymes and their roles in tuning microtubule functions

Abstract

Cellular microtubules are marked by abundant and evolutionarily conserved post-translational modifications that have the potential to tune their functions. This review focuses on the astonishing chemical complexity introduced in the tubulin heterodimer at the post-translational level and summarizes the recent advances in identifying the enzymes responsible for these modifications and deciphering the consequences of tubulin’s chemical diversity on the function of molecular motors and microtubule associated proteins.

ε-tubulin is essential in Tetrahymena thermophila for the assembly and stability of basal bodies

“…The remaining domain, the C-terminal tail, is essential as a whole, but individual mutations are viable. In aand b-tubulin this tail is the site of most post-translational modifications, is negatively charged, and provides a docking surface for microtubule-associated proteins (Duan and Gorovsky, 2002; Garnham and Roll-Mecak, 2012;Wloga and Gaertig, 2010). Unlike the tails of a-and b-tubulin, with pIs of 3.41 and 3.25 respectively, the C-terminal tail of Etu1p tail has a near neutral charge with a pI of 6.86.…”

Inhibition of HDAC6 Deacetylase Activity Increases Its Binding with Microtubules and Suppresses Microtubule Dynamic Instability in MCF-7 Cells

“…It has been recently emerging that these post-translational modifications create functionally distinct microtubules and mark them for specialized functions (1). Acetylation at Lys-40 of ␣-tubulin is mediated by acetyltransferase (2) whereas histone deacetylase 6 (HDAC6) 2 and sirtuin2 (SIRT2) catalyze the removal of the acetyl group (3)(4)(5)(6). HDAC6 is a unique class IIb mammalian HDAC that contains two homologous catalytic domains compared with one catalytic domain in other HDACs (7).…”

Crystal Structures of Tubulin Acetyltransferase Reveal a Conserved Catalytic Core and the Plasticity of the Essential N Terminus

“…They are subject to multiple levels of regulation by cellular effectors and diverse posttranslational modifications, including acetylation, detyrosination/tyrosination, polyglutamylation, and polyglycylation. These chemical modifications are thought to locally adapt microtubules for specific functions by directly modifying their dynamics or through differential recruitment of motors, microtubule-associated proteins, or signaling molecules (1,2).…”

“…TAT shows preference for tubulin already incorporated in microtubules (3,4), and acetylation is associated predominantly with stable microtubules such as those found in cilia (5,6) and axons (7). Acetylation regulates the interaction between microtubules and motors as well as membranous organelles (1). For example, kinesin 1 is recruited preferentially to neurites enriched in acetylation, and tubulin hyperacetylation via pharmacological inhibition of the tubulin deacetylase HDAC6 disrupts polarized trafficking, leading to mislocalization of neurite-specific cargoes (8).…”

“…Our work shows that TAT contains a conserved, stable catalytic core and a structurally plastic N terminus important for function. Tubulin hyperacetylation is associated with neuronal injury (1,19), making TAT an attractive target for small molecule inhibitors.…”