Article

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: 31.48). 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.

1 Follower
 · 
222 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: HS-1-associated protein X-1 (HAX1) is a multi-functional protein which was first identified as a Hematopoietic cell specific Lyn Substrate 1 (HS1)-binding protein. Although the roles of HAX1 in apoptosis have been unraveled and HAX1 has been proposed to be involved in several diseases, additional roles of HAX1 are still being identified. Here, we demonstrated that HAX1 directly interacted with cellular Inhibitor of Apoptosis Proteins (cIAPs), ubiquitin E3 ligases which regulate the abundance of cellular proteins, via ubiquitin-dependent proteasomal degradation. We showed that HAX1 promotes auto-ubiquitination and degradation of cIAPs by facilitating the intermolecular homodimerization of RING finger domain. Moreover, HAX1 regulates the non-canonical Nuclear Factor-κB (NF-κB) signaling pathway by modulating the stability of NF-κB-Inducing Kinase (NIK), which is one of the substrates of cIAPs. Taken together, these results unveil a novel role of HAX1 in the non-canonical NF-κB pathway, and provide an important clue that HAX1 is a potential therapeutic target for the treatment of cancer.
    Oncotarget 09/2014; · 6.63 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The Tumor Necrosis Factor Receptor-1 (TNFR1) is a central regulator of inflammation, cell death, and cellular proliferation. As such, alterations in TNFR1 signaling are associated with numerous diseases ranging from autoimmune syndromes to cancer. Understanding the regulation of TNFR1 signaling is therefore of considerable importance. The transduction of signaling events in the TNFR1 pathway - from ligand binding through transcriptional regulation - is regulated at nearly every step by post-translational modifications, including ubiquitination. In this review both endogenous and pharmacologic inhibitors of TNFR1 signaling, and how these impact the ubiquitin system, will be discussed. Copyright © 2014. Published by Elsevier Ltd.
    Current Opinion in Chemical Biology 11/2014; 23. DOI:10.1016/j.cbpa.2014.10.011 · 7.65 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cellular inhibitor of apoptosis 1 (cIAP1) is a ubiquitin ligase with critical roles in the control of programmed cell death and NF-κB signaling. Under normal conditions, the protein exists as an autoinhibited monomer, but proapoptotic signals lead to its dimerization, activation and proteasomal degradation. This view of cIAP1 as a binary switch has been informed by static structural studies that cannot access the protein's dynamics. Here, we use NMR spectroscopy to study micro- and millisecond motions of specific domain interfaces in human cIAP1 and use time-resolved small-angle X-ray scattering to observe the global conformational changes necessary for activation. Although motions within each interface of the 'closed' monomer are insufficient to activate cIAP1, they enable associations with catalytic partners and activation factors. We propose that these internal motions facilitate rapid peptide-induced opening and dimerization of cIAP1, which undergoes a dramatic spring-loaded structural transition.
    Nature Structural & Molecular Biology 11/2014; 21(12). DOI:10.1038/nsmb.2916 · 11.63 Impact Factor