Volume 29, No 7, Jul 2019

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 29 Issue 7, July 2019: 533-547

ORIGINAL ARTICLES

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

Shanhui Liao¹ , Girish Rajendraprasad ², Na Wang³, Susana Eibes², Jun Gao¹, Huijuan Yu¹, Gao Wu¹, Xiaoming Tu¹, Hongda Huang³,Marin Barisic ^2,4 and Chao Xu ¹

¹ Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China; ²Cell Division and Cytoskeleton, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark; ³Department of Biology, Southern University of Science and Technology, Shenzhen, China and ⁴Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
Correspondence: Hongda Huang (huanghd@sustech.edu.cn) or Marin Barisic (barisic@cancer.dk) or Chao Xu (xuchaor@ustc.edu.cn)These authors contributed equally: Shanhui Liao, Girish Rajendraprasad and Na Wang

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.

https://doi.org/10.1038/s41422-019-0187-y

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