Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter.
Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter.
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DOI：
10.1038/nature10234
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发表时间：
2011-06-19
期刊：
影响因子：
64.8
通讯作者：
Mootha, Vamsi K.
中科院分区：
文献类型：
--
作者：
Baughman, Joshua M.;Perocchi, Fabiana;Girgis, Hany S.;Plovanich, Molly;Belcher-Timme, Casey A.;Sancak, Yasemin;Bao, X. Robert;Strittmatter, Laura;Goldberger, Olga;Bogorad, Roman L.;Koteliansky, Victor;Mootha, Vamsi K.
来自不同生物的线粒体能够通过一种称为单转运体的、对钌红敏感的、膜电位依赖的机制来运输大量的钙离子。虽然单转运蛋白的生物物理性质已经被广泛研究，但它的分子组成仍然难以捉摸。我们最近使用比较蛋白质组学来鉴定MICU1(也被称为CBARA1)，这是一种含有EF-手的蛋白质，可能是单转运蛋白的调节因子。在这里，我们使用全基因组系统发育图谱、全基因组RNA共表达分析和细胞器全蛋白共表达分析来预测与MICU1功能相关的蛋白质。这三种方法都集中在一种新的预测的跨膜蛋白CCDC109A上，我们现在称之为‘线粒体钙单一转运体’(MCU)。MCU在线粒体内膜上形成低聚体，与MICU1物理上相互作用，并存在于一个大分子复合体中。在培养细胞或小鼠肝脏中沉默MCU会严重破坏线粒体对钙的摄取，而线粒体的呼吸和膜电位保持完全不变。MCU有两个预测的跨膜螺旋，它们被一个面向膜间隙的高度保守的连接子分开。该接头中的酸性残基是其充分活性所必需的。然而，S259A点突变保留了功能，但对Ru360产生了抵抗，Ru360是单转运蛋白最有效的抑制剂。我们的基因组、生理、生化和药理学数据坚定地证明了MCU是线粒体钙单转运体的重要组成部分。
Mitochondria from diverse organisms are capable of transporting large amounts of Ca2+ via a ruthenium-red-sensitive, membrane-potential-dependent mechanism called the uniporter. Although the uniporter’s biophysical properties have been studied extensively, its molecular composition remains elusive. We recently used comparative proteomics to identify MICU1 (also known as CBARA1), an EF-hand-containing protein that serves as a putative regulator of the uniporter. Here, we use whole-genome phylogenetic profiling, genome-wide RNA co-expression analysis and organelle-wide protein coexpression analysis to predict proteins functionally related to MICU1. All three methods converge on a novel predicted transmembrane protein, CCDC109A, that we now call ‘mitochondrial calcium uniporter’ (MCU). MCU forms oligomers in the mitochondrial inner membrane, physically interacts with MICU1, and resides within a large molecular weight complex. Silencing MCU in cultured cells or in vivo in mouse liver severely abrogates mitochondrial Ca2+ uptake, whereas mitochondrial respiration and membrane potential remain fully intact. MCU has two predicted transmembrane helices, which are separated by a highly conserved linker facing the intermembrane space. Acidic residues in this linker are required for its full activity. However, an S259A point mutation retains function but confers resistance to Ru360, the most potent inhibitor of the uniporter. Our genomic, physiological, biochemical and pharmacological data firmly establish MCU as an essential component of the mitochondrial Ca2+ uniporter.
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影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1186/1745-7580-4-5
发表时间：
2008-04-29
期刊：
Immunome research
影响因子：
--
作者：
Lattin JE;Schroder K;Su AI;Walker JR;Zhang J;Wiltshire T;Saijo K;Glass CK;Hume DA;Kellie S;Sweet MJ
通讯作者：
Sweet MJ
DOI：
10.1073/pnas.47.11.1744
发表时间：
1961-01-01
影响因子：
11.1
作者：
DELUCA, HF;ENGSTROM, GW
通讯作者：
ENGSTROM, GW
影响因子：
4.8
作者：
Rebres, Robert A.;Roach, Tamara I. A.;Seaman, William E.
通讯作者：
Seaman, William E.
影响因子：
64.5
作者：
Pagliarini DJ;Calvo SE;Chang B;Sheth SA;Vafai SB;Ong SE;Walford GA;Sugiana C;Boneh A;Chen WK;Hill DE;Vidal M;Evans JG;Thorburn DR;Carr SA;Mootha VK
通讯作者：
Mootha VK