Molecular basis of vasohibins-mediated detyrosination and its impact on spindle function and mitosis
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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.
Original language | English |
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Journal | Cell Research |
Volume | 29 |
Issue number | 7 |
Pages (from-to) | 533-547 |
Number of pages | 15 |
ISSN | 1001-0602 |
DOIs | |
Publication status | Published - 2019 |
Bibliographical note
Publisher Correction:: ; https://doi.org/10.1038/s41422-019-0215-y
Links
- http://europepmc.org/articles/pmc6796878?pdf=render
Final published version
ID: 226792239