Mps1 phosphorylates its N-terminal extension to relieve autoinhibition and activate the spindle assembly checkpoint Journal Article
| Authors: | Combes, G.; Barysz, H.; Garand, C.; Braga, L. G.; Alharbi, I.; Thebault, P.; Murakami, L.; Bryne, D. P.; Stankovic, S.; Eyers, P. A.; Bolanos-Garcia, V. M.; Earnshaw, W. C.; Maciejowski, J.; Jallepalli, P. V.; Elowe, S. |
| Article Title: | Mps1 phosphorylates its N-terminal extension to relieve autoinhibition and activate the spindle assembly checkpoint |
| Abstract: | Monopolar spindle 1 (Mps1) is a conserved apical kinase in the spindle assembly checkpoint (SAC) that ensures accurate segregation of chromosomes during mitosis. Mps1 undergoes extensive auto- and transphosphorylation, but the regulatory and functional consequences of these modifications remain unclear. Recent findings highlight the importance of intermolecular interactions between the N-terminal extension (NTE) of Mps1 and the Hec1 subunit of the NDC80 complex, which control Mps1 localization at kinetochores and activation of the SAC. Whether the NTE regulates other mitotic functions of Mps1 remains unknown. Here, we report that phosphorylation within the NTE contributes to Mps1 activation through relief of catalytic autoinhibition that is mediated by the NTE itself. Moreover, we find that this regulatory NTE function is independent of its role in Mps1 kinetochore recruitment. We demonstrate that the NTE autoinhibitory mechanism impinges most strongly on Mps1-dependent SAC functions and propose that Mps1 activation likely occurs sequentially through dimerization of a “prone-to-autophosphorylate” Mps1 conformer followed by autophosphorylation of the NTE prior to maximal kinase activation segment trans-autophosphorylation. Our observations underline the importance of autoregulated Mps1 activity in generation and maintenance of a robust SAC in human cells. Combes et al. demonstrate that autophosphorylation by the spindle checkpoint kinase Mps1 at its N-terminal extension relieves catalytic autoinhibition and is required for optimal checkpoint activity. This occurs independently of the role of the N-terminal extension in kinetochore binding, suggesting multiple roles for this region during mitosis. © 2018 The Author(s) |
| Keywords: | mitosis; autoactivation; autoinhibition; kinase; spindle checkpoint; kinetochore; sac; mps1 |
| Journal Title: | Current Biology |
| Volume: | 28 |
| Issue: | 6 |
| ISSN: | 0960-9822 |
| Publisher: | Cell Press |
| Date Published: | 2018-03-19 |
| Start Page: | 872 |
| End Page: | 883.e5 |
| Language: | English |
| DOI: | 10.1016/j.cub.2018.02.002 |
| PROVIDER: | scopus |
| PMCID: | PMC5863767 |
| PUBMED: | 29502948 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 June 2018 -- Source: Scopus |
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