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Abstract:
Background: The spindle assembly checkpoint (SAC) imparts fidelity to
chromosome segregation by delaying anaphase until all sister chromatid
pairs have become bipolarly attached. Mad2 is a component of the SAC
effector complex that sequesters Cdc20 to halt anaphase. In
prometaphase, Mad2 is recruited to kinetochores with the help of Mad1,
and it is activated to bind Cdc20. These events are linked to the
existence of two distinct conformers of Mad2: a closed conformer bound
to its kinetochore receptor Mad1 or its target in the checkpoint Cdc20
and an open conformer unbound to these ligands.
Results: We investigated the mechanism of Mad2 recruitment to the
kinetochore during checkpoint activation and subsequent transfer to
Cdc20. We report that a closed conformer of Mad2 constitutively bound to
Mad1, rather than Mad1 itself, is the kinetochore receptor for cytosolic
open Mad2 and show that the interaction of open and closed Mad2
conformers is essential to sustain the SAC.
Conclusions: We propose that closed Mad2 bound to Mad1 represents a
template for the conversion of open Mad2 into closed Mad2 bound to
Cdc20. This simple model, which we have named the "Mad2 template" model,
predicts a mechanism for cytosolic propagation of the spindle checkpoint
signal away from kinetochores.