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VASH1–SVBP and VASH2–SVBP generate different detyrosination profiles on microtubules

Sacnicte Ramirez-Rios,Sung Ryul Choi,Chadni Sanyal,T. Blum,C. Bosc,Fatma Krichen,E. Denarier,J. Soleilhac,Béatrice Blot,C. Janke,V. Stoppin-Mellet,M. Magiera,I. Arnal,M. Steinmetz,M. Moutin

Published 2022 in bioRxiv

ABSTRACT

The detyrosination/tyrosination cycle of α-tubulin is critical for proper cell functioning. VASH1-SVBP and VASH2-SVBP are ubiquitous enzyme complexes involved in microtubule detyrosination. However, little is known about their mode of action. Here, we show in reconstituted systems and in cells that VASH1-SVBP and VASH2-SVBP drive global and local detyrosination of microtubules, respectively. We solved the cryo-electron microscopy structure of human VASH2-SVBP bound to microtubules, revealing a different microtubule-binding configuration of its central catalytic region compared to VASH1-SVBP. We further show that the divergent mode of detyrosination between the two enzymes is correlated with the microtubule-binding properties of their disordered N- and C-terminal regions. Specifically, the N-terminal region is responsible for a significantly longer residence time of VASH2-SVBP on microtubules compared to VASH1-SVBP. We suggest that this VASH domain is critical for microtubule-detachment and diffusion of VASH-SVBP enzymes on the lattice. Together, our results suggest a mechanism by which these enzymes could generate distinct microtubule subpopulations and confined areas of detyrosinated lattices to drive various microtubule-based cellular functions. SUMMARY VASH1-SVBP and VASH2-SVBP produce global and local detyrosination patterns of microtubule lattices, respectively. These activities rely on the interplay between the N- and C-terminal disordered regions of the enzymes, which determine their differential molecular mechanism of action. GRAPHICAL ABSTRACT Schematic representation of divergent molecular mechanisms of action of VASH-SVBP detyrosination complexes.

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