Journal
SCIENCE
Volume 371, Issue 6524, Pages 67-71Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abc1152
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Funding
- Max Planck Society
- European Research Council (ERC) Advanced Investigator Grant RECEPIANCE [669686]
- DFG's Collaborative Research Centre (CRC) [1093]
- EMBO [ALTF 669-2017]
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The open and closed topologies of HORMA-domain proteins are associated with inactive and active cellular pathways, respectively. CDC20, an impervious substrate, requires simultaneous docking on several sites of the catalytic complex in order to accelerate its binding to MAD2, promoting MCC assembly. This may define a paradigm for other HORMA-controlled systems.
Open (O) and closed (C) topologies of HORMA-domain proteins are respectively associated with inactive and active states of fundamental cellular pathways. The HORMA protein O-MAD2 converts to C-MAD2 upon binding CDC20. This is rate limiting for assembly of the mitotic checkpoint complex (MCC), the effector of a checkpoint required for mitotic fidelity. A catalyst assembled at kinetochores accelerates MAD2:CDC20 association through a poorly understood mechanism. Using a reconstituted SAC system, we discovered that CDC20 is an impervious substrate for which access to MAD2 requires simultaneous docking on several sites of the catalytic complex. Our analysis indicates that the checkpoint catalyst is substrate assisted and promotes MCC assembly through spatially and temporally coordinated conformational changes in both MAD2 and CDC20. This may define a paradigm for other HORMA-controlled systems.
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