Regulation of Initiator Caspase Activity

Abstract

Apoptosis, or cell suicide, depends upon activation of the caspases, a family of cysteine proteases. Caspases, which exist as inactive proenzymes, are activated in a two-stage proteolytic cascade. Initiator caspases are activated after recruitment to ligand-bound death receptors (the extrinsic pathway) or to the apoptosome (the intrinsic pathway). The initiator caspases cleave and activate executioner caspases, which cleave various cellular constituents. Caspase-9, an initiator caspase in the intrinsic pathway, forms a homodimer in which one monomer assumes a catalytically active conformation and the other assumes an inactive conformation. In contrast to regulation of the executioner caspases, regulation of caspase-9 activity depends upon dimerization rather than upon proteolysis. Shiozaki et al. investigated the mechanism by which the X-linked inhibitor of apoptosis (XIAP) protein regulates caspase-9 and discovered that this depended upon XIAP inhibition of caspase-9 homodimerization. Structural analysis of a complex formed by regions of caspase-9 and the third baculoviral inhibitory domain (BIR3, the caspase-9 inhibiting region) of XIAP indicated that they formed a heterodimer. BIR3 interacted with the region of caspase-9 that normally mediates homodimerization and trapped the active site in a nonfunctional conformation. Mutational analysis confirmed that an obligatory monomer was catalytically inactive and that a sequence from one member of a caspase-9 dimer was required for activity of the second. Thus, XIAP both maintains one monomer of caspase-9 in an inactive form and prevents assembly of the functional dimeric protease. In related research, Boatright et al. and Donepudi et al. demonstrated that catalytic activity of caspase-8, an initiator caspase in the extrinsic pathway, also depended upon dimerization rather than upon proteolysis. E. N. Shiozaki, J. Chai, D. L. Rigotti, S. J. Riedi, P. Li, S. M. Srinivasula, E. S. Alnemri, R. Fairman, Y. Shi, Mechanism of XIAP-mediated inhibition of caspase-9. Molecular Cell 11 , 519-527 (2003). [Online Journal] K. M. Boatright, M. Renatus, F. L. Scott, S. Sperandio, H. Shin, I. M. Pederson, J,-E. Ricci, W. A. Edris, D. P. Sutherlin, D. R. Green, G. S. Salvesen, A unified model for apical caspase activation. Molecular Cell 11 , 520-541 (2003). [Online Journal] M. Donepudi, A. M. Sweeney, C. Briand, M. G. Grütter, Insights into the regulatory mechanism for caspase-8 activation. Molecular Cell 11 , 543-549 (2003). [Online Journal]