 BIR Domain | |
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| Class:Apoptosis | |
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Structure:
The typical BIR domain is composed of six α-helices, a three-stranded β-sheet, and a zinc atom chelated by three Cys and one His residues. In the complex between Smac and the XIAP-BIR3 domain, the points of contact are between a BIR domain surface groove, formed by strand B3, helix H3 and their connecting loop, and the N-terminal residues of Smac. The specificity of this contact groove is achieved through hydrogen-bond and van der Waals interactions. The XIAP-BIR3 domain also interacts with Smac in a second contact. Residues surrounding the H1 helix of the XIAP-BIR3 domain are found packed against the middle portion of the Smac helices H2 and H3. All members of the IAP family contain at least one BIR domain where it is critical for IAP function.
Structure Reference:
Wu, G. et al. (2000) Nature 408, (6815), 1008-1012. PDB: 1G73.
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Domain 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.
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Examples of Proteins:
| BIR domain protein |
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Binding partners |
| Survivin |  |
Survivin via a homotypic interaction |
| Op | |
HID, Grim, Reaper |
| D-AIP1 | |
HID, Grim |
| D-AIP2 | |
Reaper |
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Reference in part on Cell Signaling Technology Website, Reference Section on Protein Domains. We gratefully acknowledges the following contributors:
Piers Nash1, Dan Lin3, Kathleen Binns2, Clark Wells2, Rob Ingham2, Terry Kubiseski2, Bernard Liu1, Matt Smith2,3, Ivan Blasutig2,3, Maria Sierra1, Caesar Lim2,3, Michael Arc1, Jim Fawcett2 and Tony Pawson2,3.
1. Ben May Institute for Cancer Research, The University of Chicago, Chicago, Illinois, 60637, USA
2. Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada
3. Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada
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