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The structure of the BIR3 domain of cIAP1 in complex with the N-terminal peptides of SMAC and caspase-9.

Kulathila, Raviraj and Vash, Brian and Sage, David and Cornell-Kennon, Susan and Wright, Kirk and Koehn, James and Stams, Travis and Clark, Kirk and Price, Allen (2009) The structure of the BIR3 domain of cIAP1 in complex with the N-terminal peptides of SMAC and caspase-9. Acta Crystallographica. Section D, Biological crystallography, 65 (Pt 1). pp. 58-66. ISSN 1399-0047

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).

Item Type: Article
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Additional Information: archiving not allowed on institutional repository
Keywords: apoptosis; IAP; surface plasmon resonance; cancer
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Date Deposited: 14 Dec 2009 13:48
Last Modified: 31 Jan 2013 00:54
URI: https://oak.novartis.com/id/eprint/1488

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