Tubulin tyrosine ligase-like protein 4 (TTLL4)

Tubulin tyrosine ligase-like protein 4 (TTLL4) is a member of the tubulin tyrosine ligase-like (TTLL) family, functioning primarily as a glutamylase that initiates the addition of glutamate side chains to substrate proteins. While it can modify alpha-tubulin, TTLL4 has a strong preference for beta-tubulin and non-tubulin proteins, such as the histone chaperone NAP1 and the scaffold protein PELP1 (Regnard et al., 2000; Kashiwaya et al., 2010). By catalyzing the formation of an isopeptide bond between the gamma-carboxyl group of a glutamate residue on the target protein and the amino group of a free glutamate, TTLL4 modulates microtubule dynamics, molecular motor activity, and chromatin accessibility (Garnham et al., 2015; Mahara et al., 2016). In human pathology, TTLL4 is frequently overexpressed in various cancers, including pancreatic and triple-negative breast cancer, where it promotes tumor cell proliferation and metastasis through altered exosomal biogenesis and trafficking (Windhorst et al., 2020). Beyond oncology, TTLL4 is implicated in neurodegenerative disorders where the balance of tubulin polyglutamylation is disrupted, making it a promising therapeutic target for small-molecule inhibitors aimed at restoring homeostatic post-translational modifications (Bodakuntla et al., 2021).

Other names

Tubulin tyrosine ligase-like 4Tubulin monoglutamylase TTLL4Protein polyglutamylase TTLL4KIAA0173Tubulin--tyrosine ligase-like protein 4

Initiates polyglutamylation by catalyzing the ligation of a glutamate residue to the gamma-carboxyl group of an internal glutamate residue in the C-terminal tails of target proteins through an ATP-dependent process.