Mia40 targets cysteines in a hydrophobic environment to direct oxidative protein folding in the mitochondria
Mia40 targets cysteines in a hydrophobic environment to direct oxidative protein folding in the mitochondria
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DOI：
10.1038/ncomms4041
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发表时间：
2014-01-01
影响因子：
16.6
通讯作者：
Schmid, Franz X.
中科院分区：
文献类型：
--
作者：
Koch, Johanna R.;Schmid, Franz X.
Mia40催化线粒体中含二硫化物的蛋白质的氧化折叠。折叠途径是通过在Mia40及其底物之间形成第一个混合二硫化物来引导的。在这里，我们使用Cox17来阐明该反应的分子决定因素。Mia40最初参与一种动态的非共价酶-底物复合体，该复合体在几毫秒内形成并解离。Cox17的Cys36在极快的反应中形成了混合的二硫化物，这一反应受到之前与Mia40形成的络合物的限制。Cys36的反应速度比Cox17的其他三个半胱氨酸快得多，因为它邻近三个疏水残基。Mia40优先结合到疏水区域，非共价复合体的动态性质允许快速重新定位，以实现反应性半胱氨酸的最佳定位。因此，Mia40利用其底物结合部位和催化二硫化物之间的独特邻近性来选择特定的半胱氨酸来形成关键的初始混合二硫化物。
Mia40 catalyses the oxidative folding of disulphide-containing proteins in the mitochondria. The folding pathway is directed by the formation of the first mixed disulphide between Mia40 and its substrate. Here, we employ Cox17 to elucidate the molecular determinants of this reaction. Mia40 engages initially in a dynamic non-covalent enzyme-substrate complex that forms and dissociates within milliseconds. Cys36 of Cox17 forms the mixed disulphide in an extremely rapid reaction that is limited by the preceding complex formation with Mia40. Cys36 reacts much faster than the three other cysteines of Cox17, because it neighbours three hydrophobic residues. Mia40 binds preferentially to hydrophobic regions and the dynamic nature of the non-covalent complex allows rapid reorientation for an optimal positioning of the reactive cysteine. Mia40 thus uses the unique proximity between its substrate-binding site and the catalytic disulphide to select a particular cysteine for forming the critical initial mixed disulphide.