Structural insights into the pro-apoptotic function of mitochondrial serine protease HtrA2/Omi
Structural insights into the pro-apoptotic function of mitochondrial serine protease HtrA2/Omi
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DOI：
10.1038/nsb795
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发表时间：
2002-06-01
期刊：
影响因子：
--
通讯作者：
Shi, YG
中科院分区：
文献类型：
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作者：
Li, WY;Srinivasula, SM;Shi, YG
HtrA 2/Omi是哺乳动物线粒体丝氨酸蛋白酶，在细胞程序性死亡中起重要作用。然而，HtrA 2/Omi介导的细胞凋亡的基本机制仍不清楚。与细菌同源物HtrA（DegP）类似，成熟的HtrA 2蛋白含有中心丝氨酸蛋白酶结构域和C-末端PDZ结构域。HtrA 2/Omi的2.0埃晶体结构揭示了仅由丝氨酸蛋白酶结构域介导的α-形同源三聚体的形成。PDZ结构域的肽结合口袋埋在PDZ和蛋白酶结构域之间的紧密界面中。突变分析表明，单体HtrA 2/Omi突变体不能诱导细胞死亡，并且缺乏蛋白酶活性。PDZ结构域通过调节其丝氨酸蛋白酶活性来调节HtrA 2/Omi介导的细胞死亡活性。这些结构和生化观察为破译HtrA 2/Omi介导的细胞凋亡机制提供了一个重要的框架。
HtrA2/Omi, a mitchondrial serine protease in mammals, is important in programmed cell death. However, the underlining mechanism of HtrA2/Omi-mediated apoptosis remains unclear. Analogous to the bacterial homolog HtrA ( DegP) the mature HtrA2 protein contains a central serine protease domain and a C-terminal PDZ domain. The 2.0 Angstrom crystal structure of HtrA2/Omi reveals the formation of a pyramid-shaped homotrimer mediated exclusively by the serine protease domains. The peptide-binding pocket of the PDZ domain is buried in the intimate interface between the PDZ and the protease domains. Mutational analysis reveals that the monomeric HtrA2/Omi mutants are unable to induce cell death and are deficient in protease activity. The PDZ domain modulates HtrA2/Omi-mediated cell death activity by regulating its serine protease activity. These structural and biochemical observations provide an important framework for deciphering the mechanisms of HtrA2/Omi-mediated apoptosis.