Structural basis of impaired disaggregase function in the oxidation-sensitive SKD3 mutant causing 3-methylglutaconic aciduria.
Structural basis of impaired disaggregase function in the oxidation-sensitive SKD3 mutant causing 3-methylglutaconic aciduria.
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在氧化敏感的SKD3突变体中分解酶函数受损的结构基础，导致3-甲基谷氨酸酸尿。
DOI：
10.1038/s41467-023-37657-9
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发表时间：
2023-04-11
影响因子：
16.6
通讯作者：
Tsai, Francis T. F.
中科院分区：
文献类型：
--
作者：
Lee, Sukyeong;Lee, Sang Bum;Sung, Nuri;Xu, Wendy W.;Chang, Changsoo;Kim, Hyun-Eui;Catic, Andre;Tsai, Francis T. F.
线粒体对细胞和生物体的健康至关重要。为了防止损伤，线粒体已经进化出蛋白质质量控制机器来调查和维护线粒体蛋白质组。SKD 3，也称为CLPB，是一种成环的、ATP驱动的蛋白质解聚酶，对保持线粒体完整性和结构至关重要。SKD 3缺乏导致3-甲基戊烯二酸尿症VII型（MGCA 7）和婴儿早期死亡，而ATP酶结构域的突变损害蛋白质解聚，观察到的功能丧失与疾病严重程度相关。非催化性N结构域的突变如何导致疾病尚不清楚。在这里，我们表明，疾病相关的N-结构域突变，Y272 C，形成与Cys 267的分子内二硫键，并严重损害SKD 3 Y272 C在氧化条件下和活细胞中的功能。虽然在所有SKD 3亚型中都发现了Cys 267和Tyr 272，但亚型-1具有额外的α-螺旋，可能与底物结合竞争，如晶体结构分析和计算机模拟所示，强调了N结构域对SKD 3功能的重要性。线粒体SKD 3是一种必需的蛋白质解聚酶。在这里，作者解决了SKD 3Ank结构域的X射线结构，表明疾病相关突变Y272 C导致二硫键形成，在氧化条件下损害SKD 3功能。
Mitochondria are critical to cellular and organismal health. To prevent damage, mitochondria have evolved protein quality control machines to survey and maintain the mitochondrial proteome. SKD3, also known as CLPB, is a ring-forming, ATP-fueled protein disaggregase essential for preserving mitochondrial integrity and structure. SKD3 deficiency causes 3-methylglutaconic aciduria type VII (MGCA7) and early death in infants, while mutations in the ATPase domain impair protein disaggregation with the observed loss-of-function correlating with disease severity. How mutations in the non-catalytic N-domain cause disease is unknown. Here, we show that the disease-associated N-domain mutation, Y272C, forms an intramolecular disulfide bond with Cys267 and severely impairs SKD3Y272C function under oxidizing conditions and in living cells. While Cys267 and Tyr272 are found in all SKD3 isoforms, isoform-1 features an additional α-helix that may compete with substrate-binding as suggested by crystal structure analyses and in silico modeling, underscoring the importance of the N-domain to SKD3 function. Mitochondrial SKD3 is an essential protein disaggregase. Here, authors solve the X-ray structures of SKD3Ank domain suggesting that the disease-associated mutation Y272C leads to a disulfide bond formation that impairs SKD3 function under oxidizing conditions.
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线粒体膜间隙中的氧化还原环境与细胞质和基质是分开的
影响因子：
4.8
作者：
Hu, Jingjing;Dong, Lixue;Outten, Caryn E.
通讯作者：
Outten, Caryn E.
影响因子：
15.9
作者：
Fan, Yanxin;Murgia, Marta;Linder, Monika, I;Mizoguchi, Yoko;Wang, Cong;Lyszkiewicz, Marcin;Zietara, Natalia;Liu, Yanshan;Frenz, Stephanie;Sciuccati, Gabriela;Partida-Gaytan, Armando;Alizadeh, Zahra;Rezaei, Nima;Rehling, Peter;Dennerlein, Sven;Mann, Matthias;Klein, Christoph
通讯作者：
Klein, Christoph
影响因子：
4.2
作者：
Pronicka, Ewa;Ropacka-Lesiak, Mariola;Wortmann, Saskia B.
通讯作者：
Wortmann, Saskia B.
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
4.2
作者：
Kanabus, Marta;Shahni, Rojeen;Rahman, Shamima
通讯作者：
Rahman, Shamima