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IAP Antagonists Promote Cell Death Print
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.

 

A) Domain structure of the cIAP1-B3R construct. B) Crystal structure of the monomeric form of cIAP1-B3R. Domains are colored as in the primary structure diagram. Linkers between domains are colored yellow. The RING domain (orange), which is responsible for homodimerization, is sequestered on three sides by the other globular domains.


 

Work performed on ALS Beamlines 5.0.2 and 12.3.1.

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).