Churbanova Inna Y, Sevrioukova Irina F
Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697-3900, USA.
J Biol Chem. 2008 Feb 29;283(9):5622-31. doi: 10.1074/jbc.M709147200. Epub 2007 Dec 31.
Mitochondrial apoptosis-inducing factor (AIF) is a central player in the caspase-independent cell death pathway whose normal physiological function remains unclear. Our study showed that naturally folded mouse AIF very slowly reacts with NAD(P)H (k cat of 0.2-0.01 s(-1)) forming tight, dimeric, and air-stable FADH2-NAD(P) charge-transfer complexes ineffective in electron transfer. FAD reduction is accompanied by a conformational change involving AIF-specific N-terminal and regulatory 509-559 peptides and the active site His 453, and it affects susceptibility of AIF to calpain and AIF-DNA interaction, the two events critical for initiating caspase-independent apoptosis. Based on our results, we propose that formation of long lived complexes with NAD(P)H and redox reorganization may be functionally important and enable AIF to act as a redox-signaling molecule linking NAD(P)H-dependent metabolic pathways to apoptosis.
线粒体凋亡诱导因子（AIF）是不依赖半胱天冬酶的细胞死亡途径中的核心因子，其正常生理功能尚不清楚。我们的研究表明，天然折叠的小鼠AIF与NAD(P)H反应非常缓慢（催化常数为0.2 - 0.01 s(-1)），形成紧密、二聚体且对空气稳定的FADH2-NAD(P)电荷转移复合物，该复合物在电子转移中无效。FAD还原伴随着构象变化，涉及AIF特异性的N端和调控性509 - 559肽段以及活性位点His 453，并且它影响AIF对钙蛋白酶的敏感性以及AIF与DNA的相互作用，这两个事件对于启动不依赖半胱天冬酶的凋亡至关重要。基于我们的结果，我们提出与NAD(P)H形成长寿命复合物以及氧化还原重组在功能上可能很重要，并使AIF能够作为一种氧化还原信号分子，将依赖NAD(P)H的代谢途径与凋亡联系起来。
