The structure of the BIR3 domain of cIAP1 in complex with the N-terminal peptides of SMAC and caspase-9.
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).
Kulathila
Raviraj
R
Novartis Institutes for Biomedical Research Inc., USA.
Vash
Brian
B
Sage
David
D
Cornell-Kennon
Susan
S
Wright
Kirk
K
Koehn
James
J
Stams
Travis
T
Clark
Kirk
K
Price
Allen
A
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
D046912:Multiprotein Complexes; D009842:Oligopeptides; C532637:SMAC peptide; D051636:X-Linked Inhibitor of Apoptosis Protein; D053453:Caspase 9