Journal
SCIENCE
Volume 334, Issue 6054, Pages 376-380Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1207862
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Funding
- Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy (DOE) [DE-AC02-05CH11231]
- DOE Office of Biological and Environmental Research
- National Center for Research Resources, NIH [P41RR001209]
- DOE Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]
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Inhibitor of apoptosis (IAP) proteins are negative regulators of cell death. IAP family members contain RING domains that impart E3 ubiquitin ligase activity. Binding of endogenous or small-molecule antagonists to select baculovirus IAP repeat (BIR) domains within cellular IAP (cIAP) proteins promotes autoubiquitination and proteasomal degradation and so releases inhibition of apoptosis mediated by cIAP. Although the molecular details of antagonist-BIR domain interactions are well understood, it is not clear how this binding event influences the activity of the RING domain. Here biochemical and structural studies reveal that the unliganded, multidomain cIAP1 sequesters the RING domain within a compact, monomeric structure that prevents RING dimerization. Antagonist binding induces conformational rearrangements that enable RING dimerization and formation of the active E3 ligase.
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