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结构揭示了 MICU1-MICU2 对线粒体 Ca2+ 单向转运体的门控作用。

Structures reveal gatekeeping of the mitochondrial Ca uniporter by MICU1-MICU2.

机构信息

Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.

Graduate Program in Biochemistry and Structural Biology, Cell and Developmental Biology, and Molecular Biology, Weill Cornell Medicine Graduate School of Medical Sciences, New York, United States.

出版信息

Elife. 2020 Jul 15;9:e59991. doi: 10.7554/eLife.59991.

DOI:10.7554/eLife.59991
PMID:32667285
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7434445/
Abstract

The mitochondrial calcium uniporter is a Ca-gated ion channel complex that controls mitochondrial Ca entry and regulates cell metabolism. MCU and EMRE form the channel while Ca-dependent regulation is conferred by MICU1 and MICU2 through an enigmatic process. We present a cryo-EM structure of an MCU-EMRE-MICU1-MICU2 holocomplex comprising MCU and EMRE subunits from the beetle Tribolium castaneum in complex with a human MICU1-MICU2 heterodimer at 3.3 Å resolution. With analogy to how neuronal channels are blocked by protein toxins, a uniporter interaction domain on MICU1 binds to a channel receptor site comprising MCU and EMRE subunits to inhibit ion flow under resting Ca conditions. A Ca-bound structure of MICU1-MICU2 at 3.1 Å resolution indicates how Ca-dependent changes enable dynamic response to cytosolic Ca signals.

摘要

线粒体钙单向转运蛋白是一种 Ca 门控离子通道复合物，控制着线粒体 Ca 内流并调节细胞代谢。MCU 和 EMRE 形成通道，而 Ca 依赖性调节则由 MICU1 和 MICU2 通过一个神秘的过程赋予。我们展示了一个 cryo-EM 结构，其中包含来自甲虫 Tribolium castaneum 的 MCU-EMRE-MICU1-MICU2 完整复合物，其中 MCU 和 EMRE 亚基与来自人类的 MICU1-MICU2 异二聚体在 3.3 Å 的分辨率下形成复合物。通过类比神经元通道如何被蛋白毒素阻断，MICU1 上的一个单向转运蛋白相互作用域结合到由 MCU 和 EMRE 亚基组成的通道受体位点，以在静息 Ca 条件下抑制离子流。MICU1-MICU2 的 3.1 Å 分辨率的 Ca 结合结构表明，Ca 依赖性变化如何使细胞溶质 Ca 信号的动态响应成为可能。

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