Practice question

The spindle assembly checkpoint generates the Mitotic Checkpoint Complex containing closed Mad2, BubR1, Bub3 and Cdc20, which potently inhibits APC/C until all kinetochores attach. Checkpoint silencing requires active disassembly of this inhibitor once alignment completes. p31comet, also called MAD2L1BP and Trip13 adaptor, functions as dedicated MCC antagonist. Structurally mimicking Mad2, p31comet selectively binds the closed conformation of Mad2, termed C-Mad2, occupying the same interface that normally contacts BubR1 and therefore competitively extracting BubR1 from MCC. Together with AAA+ ATPase TRIP13, p31comet catalyzes the energetic conversion of C-Mad2 back to open O-Mad2, a conformer incapable of sequestering Cdc20. The resulting p31comet-C-Mad2-Cdc20 intermediate is recognized by TRIP13 which hydrolyzes ATP to unfold Mad2 safety belt. Released Cdc20 then activates APC/C for securin and cyclin B ubiquitination. p31comet also caps the Mad1-Mad2 core at kinetochores, preventing de novo generation of closed Mad2, ensuring rapid, switch-like APC/C activation and anaphase onset while preventing prolonged metaphase arrest and chromosome missegregation risks associated with persistent checkpoint signaling in mitosis. Additional feedback loops involving polo-like kinases, phosphatases and SCF-mediated degradation reinforce irreversibility and protect against premature progression that would compromise genome integrity and viability.