Molecular basis of vasohibins-mediated detyrosination and its impact on spindle function and mitosis

Cell Res. 2019 Jul;29(7):533-547. doi: 10.1038/s41422-019-0187-y.

Shanhui Liao ^# ¹, Girish Rajendraprasad ^# ², Na Wang ^# ³, Susana Eibes ², Jun Gao ¹, Huijuan Yu ¹, Gao Wu ¹, Xiaoming Tu ¹, Hongda Huang ⁴, Marin Barisic ⁵ ⁶, Chao Xu ⁷

Affiliations

1 Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China.
2 Cell Division and Cytoskeleton, Danish Cancer Society Research Center, 2100, Copenhagen, Denmark.
3 Department of Biology, Southern University of Science and Technology, Shenzhen, China.
4 Department of Biology, Southern University of Science and Technology, Shenzhen, China. huanghd@sustech.edu.cn.
5 Cell Division and Cytoskeleton, Danish Cancer Society Research Center, 2100, Copenhagen, Denmark. barisic@cancer.dk.
6 Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, 2100, Copenhagen, Denmark. barisic@cancer.dk.
7 Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China. xuchaor@ustc.edu.cn.
# Contributed equally.

PMID: 31171830 DOI: 10.1038/s41422-019-0187-y

Abstract

α-Tubulin detyrosination, largely catalyzed by vasohibins, is involved in many microtubule (MT)-related cellular events. In this study, we identified a core heterodimeric complex of human small vasohibin-binding protein (SVBP) and vasohibin 1 (VASH1) (hereafter denoted as SVBP-VASH1) that catalyzes the detyrosination of a peptide derived from C-terminus of α-tubulin. We further solved the crystal structures of the SVBP-VASH1 heterodimer alone and in complex with either an inhibitor or a mutant substrate peptide. Our structural research, complemented by biochemical and mutagenesis experiments, resulted in identification of the key residues for VASH1 binding to SVBP and α-tubulin substrate. Our in vivo experiments reveal that MT detyrosination in general, as well as the interactions between SVBP, VASH1, and α-tubulin, are critical for spindle function and accurate chromosome segregation during mitosis. Furthermore, we found that the phenotypes caused by the depletion of vasohibins were largely rescued upon co-depletion of kinesin13/MCAK, suggesting the coordination between the MT depolymerase and MT detyrosination during mitosis. Thus our work not only provides structural insights into the molecular mechanism of α-tubulin detyrosination catalyzed by SVBP-bound vasohibins, but also uncovers the key role of vasohibins-mediated MT detyrosination in spindle morphology and chromosome segregation during mitosis.

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