Ubiquitin binding modulates IAP antagonist-stimulated proteasomal degradation of c-IAP1 and c-IAP2

• DOI: 10.1042/bj20081885
• Publication Date: 2008-10-22T12:07:55Z
• Authors: John W. Blankenship; Eugene Varfolomeev; Tatiana Goncharov; Anna V. Fedorova; Donald S. Kirkpat...; Anita Izrael-Toma...; Lilian Phu; David Arnott; Mariam Aghajan; Kerry Zobel; J. Fernando Bazan; Wayne J. Fairbrother; Kurt Deshayes; Domagoj Vucic
• Keywords: XIAP; Inhibitor of apoptosis; Protein Degradation

A family of anti-apoptotic regulators known as IAP (inhibitor apoptosis) proteins interact with multiple cellular partners and inhibit apoptosis induced by a variety stimuli. c-IAP (cellular IAP) 1 2 are recruited to TNFR1 (tumour necrosis factor receptor 1)-associated signalling complexes, where they mediate receptor-induced NF-kappaB (nuclear kappaB) activation. Additionally, through their E3 ubiquitin ligase activities, c-IAP1 c-IAP2 promote proteasomal degradation NIK (NF-kappaB-inducing kinase) regulate the non-canonical pathway. In present paper, we describe novel ubiquitin-binding domain IAPs. The UBA (ubiquitin-associated) IAPs is located between BIR (baculovirus repeat) domains CARD (caspase activation recruitment domain) or RING (really interesting new gene) XIAP (X-linked respectively. binds mono-ubiquitin Lys(48)- Lys(63)-linked polyubiquitin chains low-micromolar affinities determined surface plasmon resonance isothermal titration calorimetry. NMR analysis domain-ubiquitin interaction reveals that this classical hydrophobic patch surrounding Ile(44) ubiquitin. Mutations critical amino acid residues in highly conserved MGF (Met-Gly-Phe) binding loop completely abrogate binding. These mutations do not overtly affect activity participation complex. Treatment cells antagonists leads c-IAP2. Deletion mutation decreases degradation, probably diminishing c-IAPs proteasome. results suggest may be an important mechanism for rapid turnover auto-ubiquitinated