Mechanistic basis for Sgo1-mediated centromere localization and function of the CPC |
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| Authors: | Maria Alba Abad Tanmay Gupta Michael A Hadders Amanda Meppelink J Pepijn Wopken Elizabeth Blackburn Juan Zou Anjitha Gireesh Lana Buzuk David A Kelly Toni McHugh Juri Rappsilber Susanne MA Lens A Arockia Jeyaprakash |
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| Institution: | 1. Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK ; 2. Early Cancer Institute, University of Cambridge Department of Oncology, Hutchison Research Centre, Cambridge Biomedical Campus, Cambridge, UK ; 3. Oncode Institute and Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands ; 4. Bioanalytics, Institute of Biotechnology, Technische Universität Berlin, Berlin, Germany |
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| Abstract: | Centromere association of the chromosomal passenger complex (CPC; Borealin-Survivin-INCENP-Aurora B) and Sgo1 is crucial for chromosome biorientation, a process essential for error-free chromosome segregation. Phosphorylated histone H3 Thr3 (H3T3ph; directly recognized by Survivin) and histone H2A Thr120 (H2AT120ph; indirectly recognized via Sgo1), together with CPC’s intrinsic nucleosome-binding ability, facilitate CPC centromere recruitment. However, the molecular basis for CPC–Sgo1 binding and how their physical interaction influences CPC centromere localization are lacking. Here, using an integrative structure-function approach, we show that the “histone H3-like” Sgo1 N-terminal tail-Survivin BIR domain interaction acts as a hotspot essential for CPC–Sgo1 assembly, while downstream Sgo1 residues and Borealin contribute for high-affinity binding. Disrupting Sgo1–Survivin interaction abolished CPC–Sgo1 assembly and perturbed CPC centromere localization and function. Our findings reveal that Sgo1 and H3T3ph use the same surface on Survivin to bind CPC. Hence, it is likely that these interactions take place in a spatiotemporally restricted manner, providing a rationale for the Sgo1-mediated “kinetochore-proximal” CPC centromere pool. |
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