title: CARD-mediated autoinhibition of cIAP1's E3 ligase activity suppresses cell proliferation and migration.
abstract: E3 ligases mediate the covalent attachment of ubiquitin to target proteins thereby enabling ubiquitin-dependent signaling. Unraveling how E3 ligases are regulated is important because miscontrolled ubiquitylation can lead to disease. Cellular inhibitor of apoptosis (cIAP) proteins are E3 ligases that modulate diverse biological processes such as cell survival, proliferation, and migration. Here, we have solved the structure of the caspase recruitment domain (CARD) of cIAP1 and identified that it is required for cIAP1 autoregulation. We demonstrate that the CARD inhibits activation of cIAP1's E3 activity by preventing RING dimerization, E2 binding, and E2 activation. Moreover, we show that the CARD is required to suppress cell proliferation and migration. Further, CARD-mediated autoregulation is also necessary to maximally suppress caspase-8-dependent apoptosis and vascular tree degeneration in vivo. Taken together, our data reveal mechanisms by which the E3 ligase activity of cIAP1 is controlled, and how its deregulation impacts on cell proliferation, migration and cell survival.
authors.affiliation: Chester Beatty Laboratories, The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, Fulham Road, London SW3 6JB, UK.
authors.forename: Juanita
authors.initials: J
authors.lastname: Lopez
authors.forename: Sidonie Wicky
authors.initials: SW
authors.lastname: John
authors.forename: Tencho
authors.initials: T
authors.lastname: Tenev
authors.forename: Gilles J P
authors.initials: GJ
authors.lastname: Rautureau
authors.forename: Mark G
authors.initials: MG
authors.lastname: Hinds
authors.forename: Floriana
authors.initials: F
authors.lastname: Francalanci
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wilson
authors.forename: Meike
authors.initials: M
authors.lastname: Broemer
authors.forename: Massimo M
authors.initials: MM
authors.lastname: Santoro
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Day
authors.forename: Pascal
authors.initials: P
authors.lastname: Meier
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D017434:Protein Structure, Tertiary / Q000502:physiology; D016415:Sequence Alignment; D055672:Static Electricity; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000502:physiology*; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D044767:Ubiquitin-Protein Ligases