Kamer Kimberli J, Grabarek Zenon, Mootha Vamsi K
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.
EMBO Rep. 2017 Aug;18(8):1397-1411. doi: 10.15252/embr.201643748. Epub 2017 Jun 14.
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.
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。
