CDC20 assists its catalytic incorporation in the mitotic checkpoint complex

Piano V, Alex A, Stege P, Maffini S, Stoppiello GA, Huis In 't Veld PJ, Vetter IR, Musacchio A. (2020) Science 

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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.

Proposed floatand-catch model. Left, MAD1:C-MAD2 and BUB1:BUB3 complexes associate to facilitate the O-MAD2 and CDC20 interaction. Right, (I) O-MAD2 docks on C-MAD2; (II) the safety belt of O-MAD2 unfolds but the N terminus of O-MAD2 prevents its closure; (III) the PEG motif guides the MIM in position; (IV) CDC20 promotes the conformational change of MAD2 from O- to C-MAD2 by locking the safety belt on the MIM and displacing the N terminus of MAD2; and (V) C-MAD2 bound to CDC20 is released from MAD1:C-MAD2
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