MICU1-MICU2对钙离子的高亲和力协同结合充当单向转运体的开关。
High-affinity cooperative Ca binding by MICU1-MICU2 serves as an on-off switch for the uniporter.
作者信息
Kamer Kimberli J, Grabarek Zenon, Mootha Vamsi K
机构信息
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
出版信息
EMBO Rep. 2017 Aug;18(8):1397-1411. doi: 10.15252/embr.201643748. Epub 2017 Jun 14.
Abstract
The mitochondrial calcium uniporter is a Ca-activated Ca channel that is essential for dynamic modulation of mitochondrial function in response to cellular Ca signals. It is regulated by two paralogous EF-hand proteins-MICU1 and MICU2, but the mechanism is unknown. Here, we demonstrate that both MICU1 and MICU2 are stabilized by Ca We reconstitute the MICU1-MICU2 heterodimer and demonstrate that it binds Ca cooperatively with high affinity. We discover that both MICU1 and MICU2 exhibit affinity for the mitochondria-specific lipid cardiolipin. We determine the minimum Ca concentration required for disinhibition of the uniporter in permeabilized cells and report a close match with the Ca-binding affinity of MICU1-MICU2. We conclude that cooperative, high-affinity interaction of the MICU1-MICU2 complex with Ca serves as an on-off switch, leading to a tightly controlled channel, capable of responding directly to cytosolic Ca signals.
摘要
线粒体钙单向转运体是一种钙激活的钙通道，对于响应细胞钙信号动态调节线粒体功能至关重要。它受两个同源的EF手型蛋白——线粒体钙摄取蛋白1（MICU1）和线粒体钙摄取蛋白2（MICU2）调节，但其机制尚不清楚。在此，我们证明MICU1和MICU2均由钙稳定。我们重构了MICU1-MICU2异源二聚体，并证明它以高亲和力协同结合钙。我们发现MICU1和MICU2对线粒体特异性脂质心磷脂均表现出亲和力。我们确定了通透细胞中单向转运体去抑制所需的最低钙浓度，并报告其与MICU1-MICU2的钙结合亲和力密切匹配。我们得出结论，MICU1-MICU2复合物与钙的协同、高亲和力相互作用充当一个开关，导致一个能严格控制的通道，能够直接响应胞质钙信号。
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