Structural basis of procaspase-9 recruitment by the apoptotic protease-activating factor 1
Structural basis of procaspase-9 recruitment by the apoptotic protease-activating factor 1
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作者：
Qin, HX;Srinivasula, SM;Shi, YG
Caspase-9介导的细胞凋亡（程序性细胞死亡）在所有多细胞生物的发育和稳态中发挥着核心作用。成熟的半胱天冬酶-9是由活化因子Apaf-1募集的半胱天冬酶前体衍生而来的。已分别在1.6和2.5埃分辨率下测定了Apaf-1本身的半胱天冬酶募集结构域和与半胱天冬酶原-9的前结构域复合的半胱天冬酶募集结构域的晶体结构。这些结构和其他证据表明，Apaf-1的每个分子通过两个高度带电和互补的表面形成的非保守残基与半胱氨酸蛋白酶原-9的分子相互作用;这些表面通过分子间氢键和货车德瓦尔斯相互作用的网络确定识别特异性。天冬氨酸蛋白酶原-9或Apaf-1中重要界面残基的突变防止或减少了无细胞系统中天冬氨酸蛋白酶原-9的活化。半胱天冬酶-9的野生型而非突变型前结构域完全抑制半胱天冬酶-9的催化加工。此外，同源分析秀丽隐杆线虫表明，招聘CED-3的CED-4可能是介导的同一组：保守的结构基序，与相应的变化的特异性决定残基。
Caspase-9-mediated apoptosis (programmed cell death) plays a central role in the development and homeostasis of all multicellular organisms. Mature caspase-9 is derived from its procaspase precursor as a result of recruitment by the activating factor Apaf-1. The crystal structures of the caspase-recruitment domain of Apaf-1 by itself and In complex with the prodomain of procaspase-9 have been determined at 1.6 and 2.5 Angstrom resolution, respectively. These structures and other evidence reveal that each molecule of Apaf-1 interacts with a molecule of procaspase-9 through two highly charged and complementary surfaces formed by non-conserved residues; these surfaces determine recognition specificity through networks of intermolecular hydrogen bonds and van der Waals interactions. Mutation of the important interface residues in procaspase-9 or Apaf-1 prevents or reduces activation of procaspase-9 In a cell-free system. Wild-type, but not mutant, prodomains of caspase-9 completely inhibit catalytic processing of procaspase-9. Furthermore, analysis of homologues from Caenorhabditis elegans indicates that recruitment of CED-3 by CED-4 is probably mediated by the same set of: conserved structural motifs, with a corresponding change in the specificity-determining residues.