6j7b
Crystal structure of VASH1-SVBP in complex with epoY
Structural highlights
FunctionVASH1_HUMAN Tyrosine carboxypeptidase that removes the C-terminal tyrosine residue of alpha-tubulin, thereby regulating microtubule dynamics and function (PubMed:29146869). Acts as an angiogenesis inhibitor: inhibits migration, proliferation and network formation by endothelial cells as well as angiogenesis (PubMed:15467828, PubMed:16488400, PubMed:16707096, PubMed:19204325). This inhibitory effect is selective to endothelial cells as it does not affect the migration of smooth muscle cells or fibroblasts (PubMed:15467828, PubMed:16488400, PubMed:16707096).[1] [2] [3] [4] [5] Publication Abstract from PubMedalpha-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. Molecular basis of vasohibins-mediated detyrosination and its impact on spindle function and mitosis.,Liao S, Rajendraprasad G, Wang N, Eibes S, Gao J, Yu H, Wu G, Tu X, Huang H, Barisic M, Xu C Cell Res. 2019 Jun 6. pii: 10.1038/s41422-019-0187-y. doi:, 10.1038/s41422-019-0187-y. PMID:31171830[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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