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rdf:type |
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lifeskim:mentions |
umls-concept:C0243125,
umls-concept:C0600253,
umls-concept:C0699900,
umls-concept:C0763658,
umls-concept:C1332414,
umls-concept:C1332415,
umls-concept:C1332713,
umls-concept:C1415831,
umls-concept:C1523777,
umls-concept:C1531411,
umls-concept:C2239666
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pubmed:issue |
1
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pubmed:dateCreated |
2008-12-8
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pubmed:abstractText |
A family of anti-apoptotic regulators known as IAP (inhibitor of apoptosis) proteins interact with multiple cellular partners and inhibit apoptosis induced by a variety of stimuli. c-IAP (cellular IAP) 1 and 2 are recruited to TNFR1 (tumour necrosis factor receptor 1)-associated signalling complexes, where they mediate receptor-induced NF-kappaB (nuclear factor kappaB) activation. Additionally, through their E3 ubiquitin ligase activities, c-IAP1 and c-IAP2 promote proteasomal degradation of NIK (NF-kappaB-inducing kinase) and regulate the non-canonical NF-kappaB pathway. In the present paper, we describe a novel ubiquitin-binding domain of IAPs. The UBA (ubiquitin-associated) domain of IAPs is located between the BIR (baculovirus IAP repeat) domains and the CARD (caspase activation and recruitment domain) or the RING (really interesting new gene) domain of c-IAP1 and c-IAP2 or XIAP (X-linked IAP) respectively. The c-IAP1 UBA domain binds mono-ubiquitin and Lys(48)- and Lys(63)-linked polyubiquitin chains with low-micromolar affinities as determined by surface plasmon resonance or isothermal titration calorimetry. NMR analysis of the c-IAP1 UBA domain-ubiquitin interaction reveals that this UBA domain binds the classical hydrophobic patch surrounding Ile(44) of ubiquitin. Mutations of critical amino acid residues in the highly conserved MGF (Met-Gly-Phe) binding loop of the UBA domain completely abrogate ubiquitin binding. These mutations in the UBA domain do not overtly affect the ubiquitin ligase activity of c-IAP1 or the participation of c-IAP1 and c-IAP2 in the TNFR1 signalling complex. Treatment of cells with IAP antagonists leads to proteasomal degradation of c-IAP1 and c-IAP2. Deletion or mutation of the UBA domain decreases this degradation, probably by diminishing the interaction of the c-IAPs with the proteasome. These results suggest that ubiquitin binding may be an important mechanism for rapid turnover of auto-ubiquitinated c-IAP1 and c-IAP2.
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
1470-8728
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pubmed:author |
pubmed-author:AghajanMariamM,
pubmed-author:ArnottDavidD,
pubmed-author:BazanJ FernandoJF,
pubmed-author:BlankenshipJohn WJW,
pubmed-author:DeshayesKurtK,
pubmed-author:FairbrotherWayne JWJ,
pubmed-author:FedorovaAnna VAV,
pubmed-author:GoncharovTatianaT,
pubmed-author:Izrael-TomasevicAnitaA,
pubmed-author:KirkpatrickDonald SDS,
pubmed-author:PhuLilianL,
pubmed-author:VarfolomeevEugeneE,
pubmed-author:VucicDomagojD,
pubmed-author:ZobelKerryK
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pubmed:issnType |
Electronic
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pubmed:day |
1
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pubmed:volume |
417
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
149-60
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pubmed:dateRevised |
2011-11-2
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pubmed:meshHeading |
pubmed-meshheading:18939944-Amino Acid Sequence,
pubmed-meshheading:18939944-Binding Sites,
pubmed-meshheading:18939944-Calorimetry,
pubmed-meshheading:18939944-Cell Line,
pubmed-meshheading:18939944-Cell Line, Tumor,
pubmed-meshheading:18939944-Circular Dichroism,
pubmed-meshheading:18939944-Humans,
pubmed-meshheading:18939944-Inhibitor of Apoptosis Proteins,
pubmed-meshheading:18939944-Kinetics,
pubmed-meshheading:18939944-Magnetic Resonance Spectroscopy,
pubmed-meshheading:18939944-Mass Spectrometry,
pubmed-meshheading:18939944-Molecular Sequence Data,
pubmed-meshheading:18939944-NF-kappa B,
pubmed-meshheading:18939944-Polyubiquitin,
pubmed-meshheading:18939944-Proteasome Endopeptidase Complex,
pubmed-meshheading:18939944-Protein Binding,
pubmed-meshheading:18939944-Protein Structure, Secondary,
pubmed-meshheading:18939944-Protein Structure, Tertiary,
pubmed-meshheading:18939944-Protein-Serine-Threonine Kinases,
pubmed-meshheading:18939944-Receptors, Tumor Necrosis Factor, Type I,
pubmed-meshheading:18939944-Sequence Homology, Amino Acid,
pubmed-meshheading:18939944-Surface Plasmon Resonance,
pubmed-meshheading:18939944-Ubiquitin,
pubmed-meshheading:18939944-Ubiquitination
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pubmed:year |
2009
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pubmed:articleTitle |
Ubiquitin binding modulates IAP antagonist-stimulated proteasomal degradation of c-IAP1 and c-IAP2(1).
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pubmed:affiliation |
Department of Protein Engineering, Genentech, Inc., 1 DNA Way, M/S 40, South San Francisco, CA 94080, USA.
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pubmed:publicationType |
Journal Article
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