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bioRxiv · 10.1101/2025.10.13.682252

BubR1 TPR domain supports mitotic checkpoint by promoting MCC formation and MCC-APC/C interaction

Lei, T.·Zhang, M.·Wang, Y.·Li, M.·Zhang, G.
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Abstract

BubR1 is the key component of the mitotic checkpoint, a surveillance mechanism ensures accurate chromosome segregation by facilitating the assembly of the mitotic checkpoint complex and promoting its binding to the anaphase-promoting complex/cyclosome. Although BubR1s role in SAC signaling has been extensively investigated, the function of its N-terminal tetratricopeptide repeat (TPR) domain remains poorly understood. In this study, we first established the essential role of the BubR1 TPR domain in SAC signaling. Guided by the resolved cryo-EM structure of the MCC-APC/C complex, we identified and characterized several interactions involving this domain with Mad2, Cdc20APC/C, Apc2. Furthermore, we discovered an intramolecular interaction between the TPR domain and downstream residues of BubR1, which appears to organize a structure resembling a "lasso" that incorporates four Cdc20APC/C-binding elements, thereby enhancing engagement with Cdc20 in the APC/C. Functional and biochemical analyses demonstrated that these interactions collectively promote MCC assembly and MCC-APC/C binding, enabling rapid SAC activation in response to microtubule-kinetochore attachment defects.

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Lei, T., Zhang, M., Wang, Y., Li, M., Zhang, G.. 2025-10-14. BubR1 TPR domain supports mitotic checkpoint by promoting MCC formation and MCC-APC/C interaction. https://doi.org/10.1101/2025.10.13.682252

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