Polyglutamylated

Polyglutamylation is a post-translational modification in which one or more glutamate residues are added as side chains to a substrate protein, most commonly to tubulin. The process extends existing Glu residues by forming chains of glutamates linked through their gamma-carboxyl groups, creating polyglutamate side chains that protrude from the protein surface. The modification is dynamic and regulated, influencing protein–protein interactions and cellular functions.

Enzymes and regulation

The addition of glutamate chains is catalyzed by a family of enzymes known as tubulin tyrosine ligase-like (TTLL) glutamylases. Different TTLL members have distinct substrate preferences and chain lengths, contributing to a spectrum of polyglutamylation patterns. The removal of glutamate residues is carried out by cytosolic carboxypeptidases (CCPs), which edit or reverse the modification. The balance between TTLLs and CCPs determines the degree of polyglutamylation on a given protein.

Substrates and biological roles

Tubulin is the best-characterized substrate, particularly within microtubules and cilia/flagella. Polyglutamylation of tubulin modulates interactions with microtubule-associated proteins and motor proteins, affecting processes such as axonal transport, microtubule stability, and ciliary function. In addition to tubulin, polyglutamylation has been observed on other cytoskeletal and axonemal proteins, contributing to the regulation of cellular architecture and motility.

Clinical and research relevance

Altered polyglutamylation is linked to defects in cilia, neurodegenerative disease models, and disrupted intracellular transport. Ongoing research aims to map specific TTLL and CCP activities, understand how chain length and branching influence function, and explore therapeutic possibilities for related disorders.

See also: post-translational modification, tubulin modifications, tubulin polyglutamylation.