Cryo-em structure of vash1-svbp bound to microtubules

Abstract

The dynamic tyrosination-detyrosination cycle of a-tubulin regulates microtubule functions. Perturbation of this cycle impairs mitosis, neural physiology, and cardiomyocyte contraction. The carboxypeptidases vasohibins 1 and 2 (VASH1 and VASH2), in complex with the small vasohibin-binding protein (SVBP), mediate a-tubulin detyrosination. These enzymes detyrosinate microtubules more efficiently than soluble ab-tubulin heterodimers. The structural basis for this substrate preference is not understood. Using cryo-electron microscopy (cryo-EM), we have determined the structure of human VASH1-SVBP bound to microtubules. The acidic C-terminal tail of a-tubulin binds to a positively charged groove near the active site of VASH1. VASH1 forms multiple additional contacts with the globular domain of a-tubulin, including contacts with a second a-tubulin in an adjacent protofilament. Simultaneous engagement of two protofilaments by VASH1 can only occur within the microtubule lattice, but not with free ab heterodimers. These latticespecific interactions enable preferential detyrosination of microtubules by VASH1.