title: The structure of the BIR3 domain of cIAP1 in complex with the N-terminal peptides of SMAC and caspase-9.
abstract: The inhibitor of apoptosis protein (IAP) family of molecules inhibit apoptosis through the suppression of caspase activity. It is known that the XIAP protein regulates both caspase-3 and caspase-9 through direct protein-protein interactions. Specifically, the BIR3 domain of XIAP binds to caspase-9 via a ;hotspot' interaction in which the N-terminal residues of caspase-9 bind in a shallow groove on the surface of XIAP. This interaction is regulated via SMAC, the N-terminus of which binds in the same groove, thus displacing caspase-9. The mechanism of suppression of apoptosis by cIAP1 is less clear. The structure of the BIR3 domain of cIAP1 (cIAP1-BIR3) in complex with N-terminal peptides from both SMAC and caspase-9 has been determined. The binding constants of these peptides to cIAP1-BIR3 have also been determined using the surface plasmon resonance technique. The structures show that the peptides interact with cIAP1 in the same way that they interact with XIAP: both peptides bind in a similar shallow groove in the BIR3 surface, anchored at the N-terminus by a charge-stabilized hydrogen bond. The binding data show that the SMAC and caspase-9 peptides bind with comparable affinities (85 and 48 nM, respectively).
authors.affiliation: Novartis Institutes for Biomedical Research Inc., USA.
authors.forename: Raviraj
authors.initials: R
authors.lastname: Kulathila
authors.forename: Brian
authors.initials: B
authors.lastname: Vash
authors.forename: David
authors.initials: D
authors.lastname: Sage
authors.forename: Susan
authors.initials: S
authors.lastname: Cornell-Kennon
authors.forename: Kirk
authors.initials: K
authors.lastname: Wright
authors.forename: James
authors.initials: J
authors.lastname: Koehn
authors.forename: Travis
authors.initials: T
authors.lastname: Stams
authors.forename: Kirk
authors.initials: K
authors.lastname: Clark
authors.forename: Allen
authors.initials: A
authors.lastname: Price
mesh_terms: D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D053453:Caspase 9 / Q000737:chemistry* / Q000378:metabolism; D003460:Crystallization; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D040681:Structural Homology, Protein; D020349:Surface Plasmon Resonance; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000737:chemistry* / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D009842:Oligopeptides; C532637:SMAC peptide; D051636:X-Linked Inhibitor of Apoptosis Protein; D053453:Caspase 9