夏普
凋亡抑制因子
突变
细胞凋亡
凋亡结构域抑制剂
化学
领域(数学分析)
细胞生物学
定点突变
分子生物学
突变
生物化学
生物
基因
半胱氨酸蛋白酶
程序性细胞死亡
突变体
数学分析
数学
作者
Chaohong Sun,Mengli Cai,Robert Meadows,Nan Xu,Angelo Gunasekera,Julia Herrmann,Joseph C. Wu,Stephen W. Fesik
标识
DOI:10.1074/jbc.m006226200
摘要
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 α-helices, a three-stranded β-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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