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main binding and function: The Baculovirus IAP Repeat (BIR) domain is an approximately 70 amino acid zinc-binding domain, first identified by sequence homology among proteins belonging to the Inhibitors of Apoptosis (IAP) family. Present in one to three tandem copies per protein, the BIR domain has been identified in over 80 different proteins in eukaryotic organisms. Most of what is known about BIR domains come from their role in IAP proteins. IAPs bind to and inhibit caspases, a class of cysteine proteases involved in propagating apoptotic signals within the cell. The BIR domain has been shown to be necessary for the interaction of IAP proteins with diverse proapoptotic factors, including invertebrate death inducers such as Reaper, Grim, HID and Doom from Drosophila and vertebrate and invertebrate members of the caspase family of proteases. BIR domains appear to have two potential modes of action. In the case of the inhibition of caspase-9 by XIAP, the third BIR domain of XIAP acts as a peptide binding motif that interacts with an ATPF/AVPY motif at the N-terminus of the linker peptide on the p12 small subunit of caspase-9, which becomes exposed after proteolytic activation of procaspase-9. This interaction is in turn regulated by the Smac/Diablo protein which competes for XIAP BIR3 binding by presenting a high affinity BIR3 interacting peptide, and thereby sequestering XIAP away from caspase-9. In contrast, the second BIR domain of XIAP appears to exert its anti-apoptotic effect simply by acting as a regulatory element for caspase binding while the N-terminal linker interacts with, and blocks, the substrate groove of caspase-3 and -7. This peptide lies across the capase active site in an orientation reverse to that of substrate binding. In this context, deletion of the BIR domain abrogates antiapoptotic function, possibly because in the absence of the BIR domain the adjacent peptide fails to adopt a caspase inhibitory conformation. Finally, the BIR domain appears to be capable of mediating homophilic interactions.
Structure Reference: Wu, G. et al. (2000) Nature 408, (6815), 1008À1012.
Examples of Domain Proteins:
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| The third BIR domain of XIAP, showing zinc atom and binding of Smac N-terminal residues (red). | |
