Microtubules (MTs) are composed of α/β-tubulin heterodimers and are one of three essential proteins that comprise the cytoskeleton of mammalian cells and have essential roles in cell development, growth, motility, mechanotransduction, and intracellular trafficking. Functional regulation of MTs is achieved through at least seven different post-translational modifications (PTMs) that usually occur post-polymerization and preferentially on the α/β-tubulin heterodimers of stable (vs dynamic) MTs. PTMs are highly dynamic and often reversible processes that regulate a protein’s functions, binding partners, and/or subcellular localization by addition of a chemical group or a peptide to amino acid residue(s) within the target protein1-4.
The polyglutamylation PTM, addition of variable length glutamate side-chains to primary sequence glutamate residues, was first described in the early 1990s. Glutamate residues in the C-terminal tails (CTTs) of α- and β-tubulins are the most common substrates1-6 (Fig. 1). Glutamylation enzymes are members of the tubulin tyrosine ligase-like (TTLL) family of proteins1-4,7,8. Cytosolic carboxypeptidases (CCP; a.k.a. Nna) function as deglutamylases with CCP1, 4, 5, and 6 removing glutamate side-chain residues in mammalian cells. Three enzymes (CCP1, CCP4, and CCP6) catalyze the shortening of polyglutamate chains, while CCP5 specifically removes the branching point glutamate residue1-4,9-11 (Fig. 1). Physiological polyglutamylation modifies MTs within neuronal cell bodies and processes (i.e., dendrites and axons) to regulate a variety of MT-based neuronal functions1-4.
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