Vasohibins are tubulin tyrosine carboxypeptidases that are important for neuron physiology. We solved crystal structures of human vasohibin 1 and 2 in complex with small vasohibin-binding protein (SVBP) in the absence and presence of different inhibitors and a C-terminal -tubulin peptide. In combination with functional data, we propose that SVBP acts as an activator of vasohibins. An extended groove and a distinctive surface residue patch of vasohibins define the specificity determinants for recognizing and cleaving the C-terminal tyrosine of -tubulin and for binding microtubules, respectively. The vasohibin-SVBP interaction and the ability of the enzyme complex to associate with microtubules regulate axon specification of neurons. Our results define the structural basis of tubulin detyrosination by vasohibins and show the relevance of this process for neuronal development. They further offer a unique platform for developing drugs against human conditions with abnormal tubulin tyrosination levels including cancer, heart defects and possibly brain disorders.

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