glutamylation

Glutamylation is a post-translational modification in which glutamate residues are covalently added to proteins by enzymes of the tubulin tyrosine ligase-like (TTLL) family. The modification typically occurs on the gamma-carboxyl group of a glutamate side chain on the substrate, creating either monoglutamylation or polyglutamylation, in which a chain of glutamates is extended from the initial residue. The reaction is reversible, and removal of glutamate units is carried out by deglutamylases.

The major substrates are tubulins, where polyglutamylation modulates interactions with microtubule-associated proteins and motor proteins, and influences microtubule stability and dynamics. Other substrates include components of cilia and flagella and various cytoskeletal and signaling proteins. Glutamylation is particularly enriched in ciliated cells and is linked to the regulation of ciliogenesis and ciliary motility. In neurons, proper levels of glutamylation contribute to axonal transport and neuronal development.

Enzymatic regulation involves TTLL glutamylases that add glutamate residues and cytosolic carboxypeptidase (CCP) family deglutamylases that remove them, creating a dynamic and reversible modification. The balance of addition and removal is important for cellular architecture and function. Misregulation of glutamylation has been associated with ciliopathies and neurodegenerative disease models, highlighting its physiological importance.

Detection and study commonly employ specific antibodies against polyglutamylated epitopes, mass spectrometry to identify modification sites, and genetic models that alter TTLL or CCP enzyme activity. Glutamylation is conserved across eukaryotes, reflecting its fundamental role in regulating cytoskeletal and ciliary biology.