Antagonists Induce a Conformational Change in cIAP1 That Promotes Autoubiquitination

Department of Early Discovery Biochemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
Science (Impact Factor: 33.61). 10/2011; 334(6054):376-80. DOI: 10.1126/science.1207862
Source: PubMed

ABSTRACT 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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    • "cIAP1 and cIAP2 are involved in degradation of the MAP3 kinase, NFB inducing kinase (NIK) in the NFκB pathway (23, 26–29), and contribute to activation of the classical NFκB pathway by tumor necrosis factor (TNF) stimulation (30–32). Besides preventing the XIAP interaction with caspases, SMAC mimetics induce activation of the NFκB pathway by binding to cIAP1 and cIAP2 and stimulating the E3 ubiquitin-ligase activity of the cIAP proteins (33). "
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    • "The above observations that LCL85 does not alter Fas level suggests that LCL85 may target mediators of the Fas-mediated apoptosis signaling pathways. IAPs are potent inhibitors of apoptosis, including Fas-mediated apoptosis [35-37]. To determine whether IAPs play a role in metastatic human colon carcinoma apoptosis resistance, we tested the effects of IAP-specific inhibitor BV6 on metastatic human colon carcinoma cells. "
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    • "In addition, discovery of SMAC-mimicking IAP antagonist compounds that target c-IAP protein for proteasomal degradation greatly aided the affirmation of c-IAPs as E3 ligases for NIK (31, 32). IAP antagonist treatment triggers rapid conformational change in c-IAP proteins that elevates their ubiquitin ligase activity leading to proteasomal degradation (53, 54). Some cells treated with these agents secrete a variety of NF-κB regulated inflammatory cytokines over a prolonged period even in the absence of cell death (55, 56). "
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