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NMR Structure and Mutagenesis of the Third Bir Domain of the Inhibitor of Apoptosis Protein XIAP
Open accessAbstract
The inhibitor of apoptosis proteins (IAPs) regulate the caspase family of cysteine proteases, which play an important role in the execution of programmed cell death. Human X-linked inhibitor of apoptosis protein (XIAP) is a potent inhibitor of caspases-3, -7, and -9. Here we show that the Bir3 domain is the minimal region of XIAP that is needed for potent caspase-9 inhibition. The three-dimensional structure of the Bir3 domain of XIAP, determined by NMR spectroscopy, resembles a classical zinc finger and consists of five alpha-helices, a three-stranded beta-sheet, and a zinc atom chelated to three cysteines and one histidine. The structure of the Bir3 domain is similar to that of the Bir2 domain of XIAP but differs from the previously determined structure of the Bir3 domain of MIHB. Based on site-directed mutagenesis, we have identified the regions of the Bir3 domain of XIAP that are important for inhibiting caspase-9. Despite the structural similarities of the Bir2 and Bir3 domain of XIAP, a different set of residues were found to be critical for inhibiting the individual caspases. These results suggest that XIAP inhibits caspase-3 and caspase-9 in a different manner.
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Cites
Apoptosis in the Pathogenesis and Treatment of Disease
Thompson, C. B. (1995) · Science · doi:10.1126/science.7878464 · Cited by 6,524
Protein backbone angle restraints from searching a database for chemical shift and sequence homology
Cornilescu, G., Delaglio, F., & Bax, A. (1999) · Journal of Biomolecular NMR · doi:10.1023/a:1008392405740 · Cited by 2,957
Cited by
IAP proteins: blocking the road to death's door
Salvesen, G. S., & Duckett, C. S. (2002) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm830 · Cited by 1,756
Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family
Eckelman, B. P., Salvesen, G. S., & Scott, F. L. (2006) · The EMBO Reports · doi:10.1038/sj.embor.7400795 · Cited by 813
Bratton, S. B., Walker, G., Srinivasula, S. M., Sun, X., Butterworth, M., Alnemri, E. S., & Cohen, G. M. (2001) · The EMBO Journal · doi:10.1093/emboj/20.5.998 · Cited by 406
The Human Anti-apoptotic Proteins cIAP1 and cIAP2 Bind but Do Not Inhibit Caspases
Eckelman, B. P., & Salvesen, G. S. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m510863200 · Cited by 391
Flygare, J. A., Beresini, M., Budha, N., Chan, H., Chan, I. T., Cheeti, S., Cohen, F., Deshayes, K., Doerner, K., Eckhardt, S. G., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm300060k · Cited by 252
Metadata
- Authors
- Sun, C., Cai, M., Meadows, R. P., Xu, N., Gunasekera, A. H., Herrmann, J., Wu, J. C., & Fesik, S. W.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-10
- Volume
- 275
- Issue
- 43
- Pages
- 33777-33781
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2014196693
- Cited by
- 254
- References
- 2
- FWCI
- 8.11
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Sun, C., Cai, M., Meadows, R. P., Xu, N., Gunasekera, A. H., Herrmann, J., Wu, J. C., & Fesik, S. W. (2000). NMR Structure and Mutagenesis of the Third Bir Domain of the Inhibitor of Apoptosis Protein XIAP. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m006226200
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