Solving the 50-years-old puzzle of the mechanism of tubulin detyrosination

Microtubules are a major component of the cytoskeleton and can accumulate a plethora of modifications. The microtubule detyrosination cycle is one of these modifications; it involves the enzymatic removal of the C-terminal tyrosine of α-tubulin on assembled microtubules and the re-ligation of tyrosine on detyrosinated tubulin dimers. This modification cycle has been implicated in cardiac disease, neuronal development, and mitotic defects. The enzymes responsible for microtubule detyrosination remains a long-sought mystery for well-over four decades since the biochemical process of detyrosination was described. The vasohibins and their co-factor Small Vasohibin Binding Protein (SVBP), are cysteine peptidases which were originally known as extracellular angiogenesis regulators, and were the first tubulin detyrosinases we discovered. Later, the Microtubule-Associated Tyrosine CArboxyPeptidase (MATCAP) and a close homologue (TMCP2) were identified as zinc metalloproteases that can cleave α (and β)tubulin tails. The structures of the catalytic domains of members of the two evolutionary unrelated enzyme families were determined by X-ray crystallography, establishing the corresponding cleavage mechanisms. Both families act preferentially on microtubules rather than on tubulin dimers, and the cryo-electron microscopy structures of vasohibins and MATCAP bound to microtubules, were key to understand fundamental differences: the vasohibins catalytic domain interacts both with the α-tubulin monomer whose tail will be cleaved and with α-tubulin of the adjacent protofilament, but MATCAP binds to adjacent tubulin dimers along a single protofilament. The current information is key to further study how these enzymes interplay with other modifications and define the tubulin code.