Posttranslational modification of microtubules by the MATCAP detyrosinase

The detyrosination-tyrosination cycle, removal and re-ligation of the C-terminal tyrosine of a-tubulin, has been implicated in cognitive, cardiac and mitotic defects. The enzymatic origin of detyrosination was only partially explained by the recently discovered Vasohibin-SVBP complex. Here, we use genetic screens to identify an unannotated protein, MATCAP, as remaining detyrosinating enzyme. X-ray crystallography and cryo-EM structures establish MATCAP's cleaving mechanism, substrate specificity, and microtubule recognition, all distinct from Vasohibins. Paradoxically, while abrogation of tyrosine re-ligation is lethal in mice, co-deletion of MATCAP and SVBP is not. Although viable, defective detyrosination causes microcephaly and abnormal behavior. MATCAP is the last component of the detyrosination-tyrosination cycle, revealing the importance of this modification in brain formation and suggesting the need of tyrosinated tubulin for life in vertebrates.