Structural Mad-ness

The spindle checkpoint is turned on when unattached kinetochores generate a signal that inhibits the anaphase-promoting complex (APC) preventing premature chromosome separation. Now, Hongtao Yu and colleagues (University of Texas Southwestern Medical Center, Dallas, TX) have shown that conformational changes in the protein Mad2 are important in triggering this checkpoint pathway.

Monomeric Mad2 is recruited to the kinetochore when it forms a complex with Mad1. Mad2 can also associate with Cdc20, an APC activator, thereby inhibiting Cdc20 and the APC.

Mad2 is constitutively present in the cell, but does not always inhibit Cdc20. Yu set out to determine the basis of inhibition by analyzing the structure of bound and unbound Mad2. NMR structures of free Mad2 and Mad2 bound to a Mad2-binding peptide (MBP1) revealed a striking shift in the conformation of the protein...