Mps1 dimerization and multisite interactions with Ndc80 complex enable responsive spindle assembly checkpoint
Ping Gui1,2, Divine M Sedzro1, Xiao Yuan1
1MOE Key Laboratory of Membraneless Organelle and Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei 230027, China.
Abstract:
Error-free mitosis depends on accurate chromosome attachment to spindle microtubules, which is monitored by the spindle assembly checkpoint (SAC) signaling. As an upstream factor of SAC, the precise and dynamic kinetochore localization of Mps1 kinase is critical for initiating and silencing SAC signaling. However, the underlying molecular mechanism remains elusive. Here, we demonstrated that the multisite interactions between Mps1 and Ndc80 complex (Ndc80C) govern Mps1 kinetochore targeting. Importantly, we identified direct interaction between Mps1 tetratricopeptide repeat domain and Ndc80C. We further identified that Mps1 C-terminal fragment, which contains the protein kinase domain and C-tail, enhances Mps1 kinetochore localization. Mechanistically, Mps1 C-terminal fragment mediates its dimerization. Perturbation of C-tail attenuates the kinetochore targeting and activity of Mps1, leading to aberrant mitosis due to compromised SAC function. Taken together, our study highlights the importance of Mps1 dimerization and multisite interactions with Ndc80C in enabling responsive SAC signaling.
Insights
Accurate cell division relies on Mps1 kinase localization to kinetochores, regulated by interactions with the Ndc80 complex. This study reveals how Mps1 dimerization and multisite binding control its targeting, ensuring proper spindle assembly checkpoint function.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- Accurate chromosome segregation during mitosis is crucial for genomic stability.
- The spindle assembly checkpoint (SAC) prevents aneuploidy by monitoring chromosome-microtubule attachments.
- Mps1 kinase is a key upstream regulator of SAC, requiring precise kinetochore localization.
Purpose of the Study:
- To elucidate the molecular mechanisms governing Mps1 kinase kinetochore targeting.
- To investigate the role of Mps1-Ndc80 complex interactions in SAC regulation.
- To understand how Mps1 dimerization and its C-terminal region contribute to SAC function.
Main Methods:
- Biochemical assays to identify protein-protein interactions.
- In vitro and in vivo studies of Mps1 and Ndc80 complex binding.
- Analysis of Mps1 kinetochore localization and SAC activity upon perturbation.
Main Results:
- Multisite interactions between Mps1 and the Ndc80 complex dictate Mps1 kinetochore localization.
- Direct interaction was identified between the Mps1 tetratricopeptide repeat domain and the Ndc80 complex.
- Mps1 dimerization, mediated by its C-terminal fragment, enhances kinetochore targeting and SAC activity.
Conclusions:
- Mps1 dimerization and its multisite interactions with the Ndc80 complex are essential for robust SAC signaling.
- Perturbing Mps1 C-tail function compromises kinetochore targeting and leads to mitotic errors.
- These findings provide critical insights into the regulation of Mps1 kinase activity for error-free mitosis.
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