Human mitochondrial cytochrome c oxidase assembly factor COX18 acts transiently as a membrane insertase within the subunit 2 maturation module
Human mitochondrial cytochrome c oxidase assembly factor COX18 acts transiently as a membrane insertase within the subunit 2 maturation module
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DOI：
10.1074/jbc.m117.778514
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发表时间：
2017-05-12
影响因子：
4.8
通讯作者：
Barrientos, Antoni
中科院分区：
文献类型：
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作者：
Bourens, Myriam;Barrientos, Antoni
线粒体细胞色素c氧化酶或呼吸链复合物IV（CIV）组装缺陷是人类线粒体疾病的常见原因。具体地说，四个保守的组装因子中的突变影响了coxon编码的催化核心亚基2（COX 2）的生物发生，导致肌病。这些因素提供了新合成的COX 2（肌张力障碍-共济失调综合征蛋白COX 20）的稳定性，一种具有两个跨膜结构域的蛋白质，以及其铜中心Cu-A（心肌病蛋白SCO 1，SCO 2和COA 6）的成熟。COX 18是属于膜蛋白插入酶Oxa 1家族的另外的COX 2组装因子。在这里，我们使用基因编辑方法来产生人COX 18敲除HEK 293 T细胞系，该细胞系显示出孤立的完全CIV缺陷。我们证明，COX 20稳定COX 2在插入其N-近端跨膜结构域，随后，COX 18瞬时与COX 2相互作用，以促进跨内膜的COX 2的C-尾，包含apo-CuA网站的易位。COX 18从该复合物中的释放与SCO 1-SCO 2-COA 6铜代谢模块与COX 2-COX 20的结合相一致，以完成COX 2的生物合成。因此，COX 18是一个新的候选人筛选线粒体疾病与孤立的CIV缺乏症。
Defects in mitochondrial cytochrome c oxidase or respiratory chain complex IV (CIV) assembly are a frequent cause of human mitochondrial disorders. Specifically, mutations in four conserved assembly factors impinging the biogenesis of the mitochondrion-encoded catalytic core subunit 2 (COX2) result in myopathies. These factors afford stability of newly synthesized COX2(the dystonia-ataxia syndrome protein COX20), a protein with two transmembrane domains, and maturation of its copper center, Cu-A (cardiomyopathy proteins SCO1, SCO2, and COA6). COX18 is an additional COX2 assembly factor that belongs to the Oxa1 family of membrane protein insertases. Here, we used a gene-editing approach to generate a human COX18 knock-out HEK293T cell line that displays isolated complete CIV deficiency. We demonstrate that COX20 stabilizes COX2 during insertion of its N-proximal transmembrane domain, and subsequently, COX18 transiently interacts with COX2 to promote translocation across the inner membrane of the COX2 C-tail that contains the apo-CuA site. The release of COX18 from this complex coincides with the binding of the SCO1-SCO2-COA6 copper metallation module to COX2-COX20 to finalize COX2 biogenesis. Therefore, COX18 is a new candidate when screening for mitochondrial disorders associated with isolated CIV deficiency.