Dimerization of MICU Proteins Controls Ca2 Influx through the Mitochondrial Ca2 Uniporter
Dimerization of MICU Proteins Controls Ca2 Influx through the Mitochondrial Ca2 Uniporter
复制标题
MICU 蛋白的二聚化通过线粒体 Ca2 Uniporter 控制 Ca2 流入
DOI：
10.1016/j.celrep.2019.01.022
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发表时间：
2019
期刊：
影响因子：
8.8
通讯作者：
Shen Yuequan
中科院分区：
文献类型：
--
作者：
Xing Yangfei;Wang Mingfei;Wang Jia;Nie Zhenzhen;Wu Guangyan;Yang Xue;Shen Yuequan
线粒体钙单转运体复合体(MCUC)负责钙离子内流到线粒体基质中，在线粒体的各种功能中起着关键作用。真核生物MCUC由多个亚基组成，其钙内流活动受线粒体钙摄取1(MICU1)及其类似亚基(MICU2和MICU3)调控。然而，潜在的机制仍不清楚。在这里，我们测定了智人MICU2和MICU3的多重晶体结构。我们的数据表明，不同的MICU蛋白N结构域决定了特定类型的MICU二聚体，这些二聚体在低细胞内钙水平时对线粒体钙摄取起相反的作用。相反，在细胞内高钙水平下，所有MICU蛋白都经历了钙结合诱导的二聚体重排，从而释放了对MCUC成孔亚基的抑制，促进了大量钙的内流。综上所述，我们的结果阐明了MICU蛋白调节线粒体钙摄取的微妙机制。
The mitochondrial Ca2+uniporter complex (MCUC) is responsible for Ca2+influx into the mitochondrial matrix, playing critical roles in various mitochondrial functions. Eukaryotic MCUC consists of multiple subunits, and its Ca2+influx activity is controlled by regulatory subunits, including mitochondrial Ca2+uptake 1 (MICU1) and its paralogs (MICU2 and MICU3). However, the underlying mechanism remains unclear. Here, we determined multiple crystal structures of MICU2 and MICU3 fromHomo sapiens. Our data demonstrate that distinct MICU protein N-domains determine the specific type of MICU dimers that perform the opposing roles in mitochondrial Ca2+uptake at low cytosolic Ca2+levels. In contrast, at high cytosolic Ca2+levels, all MICU proteins undergo dimer rearrangement induced by Ca2+binding, which releases the suppression of the MCUC pore-forming subunit and promotes the influx of large amounts of Ca2+. Altogether, our results elucidate the delicate mechanism of mitochondrial Ca2+uptake regulation by MICU proteins.