TTLL6 is a polyglutamylase enzyme that catalyzes ATP-dependent addition of polyglutamate chains to tubulin and non-tubulin proteins, preferentially targeting α-tubulin tails over β-tubulin tails 1. The enzyme employs a sophisticated quadrivalent recognition mechanism, binding to β-tubulin subunits while modifying α-tails of longitudinally adjacent dimers, and reads out existing β-tail glutamylation to create positive feedback loops that generate localized microtubule modification patterns 1. TTLL6 promotes tubulin polyglutamylation which stimulates spastin-mediated microtubule severing and is essential for ciliary structure and motility 2. In disease contexts, TTLL6 plays complex roles: it contributes to neurodegeneration when Tau missorting leads to TTLL6 mislocalization and excessive microtubule severing in Alzheimer's disease 3, while paradoxically promoting cancer cell survival by supporting mitotic spindle function 4. TTLL6 also modifies non-tubulin substrates like Mad2, regulating megakaryopoiesis 5, and shows unique microtubule-destabilizing effects among TTLL family members 6. The enzyme is expressed in various tissues including pancreatic islets and oocytes, suggesting broad physiological importance 78.