凋亡体
细胞色素c
细胞色素
半胱氨酸蛋白酶-9
结合位点
生物
半胱氨酸蛋白酶
立体化学
生物物理学
化学
细胞生物学
生物化学
细胞凋亡
程序性细胞死亡
酶
作者
Ali-Reza Noori,Amin Tashakor,Maryam Nikkhah,Leif A. Eriksson,Saman Hosseinkhani,Howard O. Fearnhead
出处
期刊:Biochimie
[Elsevier]
日期:2021-01-01
卷期号:180: 23-29
被引量:17
标识
DOI:10.1016/j.biochi.2020.10.013
摘要
Split luciferase complementary assay has been used to investigate the effect of WD domain deletion on Apaf-1 oligomerization. Apaf-1 is an adaptor molecule in formation of apoptosome that activates caspase-9, an activation that is a key event in the mitochondrial cell death pathway. Structural studies suggest that normally Apaf-1 is held in an inactive conformation by intramolecular interactions between Apaf-1’s nucleotide binding domain and one of its WD40 domains (WD1). In the prevailing model of Apaf-1 activation, cytochrome c binds to sites in WD1 and in Apaf-1’s second WD40 domain (WD2), moving WD1 and WD2 closer together and rotating WD1 away from the nucleotide binding domain. This allows Apaf-1 to bind dATP or ATP and to form the apoptosome, which activates caspase-9. This model predicts that cytochrome c binding to both WD domains is necessary for apoptosome formation and that an Apaf-1 with only WD1 will be locked in an inactive conformation that cannot be activated by cytochrome c. Here we investigated the effect of removing one WD domain (Apaf-1 1–921) on Apaf-1 interactions and caspase activation. Apaf-1 1–921 could not activate caspase-9, even in the presence of cytochrome c. These data show that a single WD domain is sufficient to lock Apaf-1 in an inactive state and this state cannot be altered by cytochrome c.
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