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Schlagwörter:
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Zusammenfassung:
The spindle checkpoint protein Mad1 recruits Mad2 to unattached
kinetochores and is essential for Mad2-Cdc20 complex formation in vivo
but not in vitro. The crystal structure of the Mad1-Mad2 complex reveals
an asymmetric tetramer, with elongated Mad1 monomers parting from a
coiled-coil to form two connected sub-complexes with Mad2 The Mad2
C-terminal tails are hinged mobile elements wrapping around the
elongated ligands like molecular 'safety belts'. We show that Mad1 is a
competitive inhibitor of the Mad2-Cdc20 complex, and propose that the
Mad1-Mad2 complex acts as a regulated gate to control Mad2 release for
Cdc20 binding. Mad1-Mad2 is strongly stabilized in the tetramer, but a
1:1 Mad1-Mad2 complex slowly releases Mad2 for Cdc20 binding, driven by
favourable binding energies. Thus, the rate of Mad2 binding to Cdc20
during checkpoint activation may be regulated by conformational changes
that destabilize the tetrameric Mad1-Mad2 assembly to promote Mad2
release. We also show that unlocking the Mad2 C-terminal tail is
required for ligand release from Mad2, and that the 'safety belt'
mechanism may prolong the lifetime of Mad2-ligand complexes.
