MAD contortions: conformational dimerization boosts spindle checkpoint signaling

Almost two decades after their identification, the components of the mitotic checkpoint are finally revealing their structural secrets. The activation of Mad2, a central piece of the checkpoint protein machinery, is linked to the rare ability of this protein to adopt two distinct topologies. Current models of checkpoint function propose that the topological transition between the two states of Mad2 is rate limiting for checkpoint activation and is accelerated through a self-activation process based on the direct interaction of the two Mad2 conformers. These models add a molecular framework to an old theory that depicts kinetochores as catalysts in the generation of the mitotic checkpoint signal.