Molecular basis of vasohibins-mediated detyrosination and its impact on spindle function and mitosis
Molecular basis of vasohibins-mediated detyrosination and its impact on spindle function and mitosis
复制标题
血管抑制素介导的去酪氨酸化的分子基础及其对纺锤体功能和有丝分裂的影响。
DOI：
10.1038/s41422-019-0187-y
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发表时间：
2019-07-01
期刊：
影响因子：
44.1
通讯作者：
Xu, Chao
中科院分区：
文献类型：
--
作者：
Liao, Shanhui;Rajendraprasad, Girish;Xu, Chao
alpha-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 alpha-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 alpha-tubulin substrate. Our in vivo experiments reveal that MT detyrosination in general, as well as the interactions between SVBP, VASH1, and alpha-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 alpha-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.
