A family of carboxypeptidases catalyzing α- and β-tubulin tail processing and deglutamylation.
Nicot S
et al.
Sci Adv 2023 Sep;9(37)eadi7838
Nicot S, Gillard G, Impheng H, Joachimiak E, Urbach S, Mochizuki K, Wloga D, Juge F, Rogowski K.
Sci Adv 2023 Sep;9(37)eadi7838
Abstract: Tubulin posttranslational modifications represent an important mechanism involved in the regulation of microtubule functions. The most widespread among them are detyrosination, α∆2-tubulin, and polyglutamylation. Here, we describe a family of tubulin-modifying enzymes composed of two closely related proteins, KIAA0895L and KIAA0895, which have tubulin metallocarboxypeptidase activity and thus were termed TMCP1 and TMCP2, respectively. We show that TMCP1 (also known as MATCAP) acts as α-tubulin detyrosinase that also catalyzes α∆2-tubulin. In contrast, TMCP2 preferentially modifies βI-tubulin by removing three amino acids from its C terminus, generating previously unknown βI∆3 modification. We show that βI∆3-tubulin is mostly found on centrioles and mitotic spindles and in cilia. Moreover, we demonstrate that TMCPs also remove posttranslational polyglutamylation and thus act as tubulin deglutamylases. Together, our study describes the identification and comprehensive biochemical analysis of a previously unknown type of tubulin-modifying enzymes involved in the processing of α- and β-tubulin C-terminal tails and deglutamylation.
Posttranslational modification of microtubules by the MATCAP detyrosinase.
Landskron L
et al.
Science 2022 May;376(6595)eabn6020
Landskron L, Bak J, Adamopoulos A, Kaplani K, Moraiti M, van den Hengel LG, Song JY, Bleijerveld OB, Nieuwenhuis J, Heidebrecht T, Henneman L, Moutin MJ, Barisic M, Taraviras S, Perrakis A, Brummelkamp TR.
Science 2022 May;376(6595)eabn6020
Abstract: The detyrosination-tyrosination cycle involves the removal and religation of the C-terminal tyrosine of α-tubulin and is implicated in cognitive, cardiac, and mitotic defects. The vasohibin-small vasohibin-binding protein (SVBP) complex underlies much, but not all, detyrosination. We used haploid genetic screens to identify an unannotated protein, microtubule associated tyrosine carboxypeptidase (MATCAP), as a remaining detyrosinating enzyme. X-ray crystallography and cryo-electron microscopy structures established MATCAP's cleaving mechanism, substrate specificity, and microtubule recognition. Paradoxically, whereas abrogation of tyrosine religation is lethal in mice, codeletion of MATCAP and SVBP is not. Although viable, defective detyrosination caused microcephaly, associated with proliferative defects during neurogenesis, and abnormal behavior. Thus, MATCAP is a missing component of the detyrosination-tyrosination cycle, revealing the importance of this modification in brain formation.
