|IAP Antagonists Promote Cell Death|
|Thursday, 02 August 2012 11:19|
Apoptosis, or programmed cell death, is a normal process for most cells in multicellular organisms. Inhibitor of apoptosis (IAP) proteins suppress apoptosis and are over-expressed in human cancer cells, causing resistance to cytotoxic therapies. An IAP antagonist can mitigate the anti-apoptotic functions of IAPs, spurring trials on IAP-targeting therapeutics that mimic endogenous IAP antagonists. To understand the mechanisms at work here, Genentech researchers investigated the structure of cellular IAP1 (cIAP1) BIR3-RING (B3R). When IAP antagonists bind to the BIR3 domain of cIAP1, a RING-based dimer forms, stimulating the addition of ubiquitin to the target protein substrate, thus marking it for degradation by the cell's proteasome.
An x-ray crystal structure of monomeric cIAP1-B3R revealed a wrapped conformation in which the RING domain is sequestered by the other domains. SAXS-derived ab initio models of three cIAP1-B3R dimer constructs revealed extended dimeric structures with the RING-RING dimer at the center of the complex. These structural and biochemical data show that in the absence of antagonists, cIAP1 is compact and monomeric. Upon disruption of the BIR3:RING interface by antagonist binding, the monomer unwraps, allowing RING:RING dimerization and marking the cell for apoptosis.
Citation: E.C. Dueber, A.J. Schoeffler, A. Lingel, J.M. Elliott, A.V. Fedorova, A.M. Giannetti, K. Zobel, B. Maurer, E. Varfolomeev, P. Wu, H.J.A. Wallweber, S.G. Hymowitz, K. Deshayes, D. Vucic, and W.J. Fairbrother, "Antagonists Induce a Conformational Change in cIAP1 That Promotes Autoubiquitination," Science 334, 376 (2011).