title: The ubiquitin-associated domain of cellular inhibitor of apoptosis proteins facilitates ubiquitylation.
abstract: The cellular inhibitor of apoptosis (cIAP) proteins are essential RING E3 ubiquitin ligases that regulate apoptosis and inflammatory responses. cIAPs contain a ubiquitin-associated (UBA) domain that binds ubiquitin and is implicated in the regulation of cell survival and proteasomal degradation. Here we show that mutation of the MGF and LL motifs in the UBA domain of cIAP1 caused unfolding and increased cIAP1 multimonoubiquitylation. By developing a UBA mutant that disrupted ubiquitin binding but not the structure of the UBA domain, we found that the UBA domain enhances cIAP1 and cIAP2 ubiquitylation. We demonstrate that the UBA domain binds to the UbcH5b∼Ub conjugate, and this promotes RING domain-dependent monoubiquitylation. This study establishes ubiquitin-binding modules, such as the UBA domain, as important regulatory modules that can fine tune the activity of E3 ligases.
authors: From the Department of Biochemistry, Otago School of Medical Sciences, University of Otago, Dunedin 9054, New Zealand.
authors: Rhesa
authors: R
authors: Budhidarmo
authors: From the Department of Biochemistry, Otago School of Medical Sciences, University of Otago, Dunedin 9054, New Zealand catherine.day@otago.ac.nz.
authors: Catherine L
authors: CL
authors: Day
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis / Q000235:genetics; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D060066:Protein Interaction Maps / Q000235:genetics*; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D025801:Ubiquitin / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics*
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex
keywords: Apoptosis; Protein-Protein Interaction; RING; Ubiquitin; Ubiquitin Ligase; Ubiquitin-conjugating Enzyme (E2 Enzyme); cIAP