Dimer formation drives the activation of the cell death protease caspase 9

A critical step in the induction of apoptosis is the activation of the apop totic initiator caspase 9. We show that at its normal physiological concent ration, caspase 9 is primarily an inactive monomer (zymogen), and that acti vity is associated with a dimeric species. At the high concentrations used for crystal formation, caspase 9 is dimeric, and the structure reveals two very different active-site conformations within each dimer. One site closel y resembles the catalytically competent sites of other caspases, whereas in the second, expulsion of the "activation loop" disrupts the catalytic mach inery. We propose that the inactive domain resembles monomeric caspase 9. A ctivation is induced by dimerization, with interactions at the dimer interf ace promoting reorientation of the activation loop. These observations supp ort a model in which recruitment by Apaf-1 creates high local concentration s of caspase 9 to provide a pathway for dimer-induced activation.