Structures reveal gatekeeping of the mitochondrial Ca2+ uniporter by MICU1-MICU2

作者：Chongyuan Wang, Agata Jacewicz, Bryce D. Delgado, Rozbeh Baradaran, Stephen B. Long · 发表于：eLife · 年份：2020 · DOI：10.7554/elife.59991 · 被引用次数：61 · 研究领域：Mitochondrial Function and Pathology、ATP Synthase and ATPases Research、Cell death mechanisms and regulation

The mitochondrial calcium uniporter is a Ca 2+ -gated ion channel complex that controls mitochondrial Ca 2+ entry and regulates cell metabolism. MCU and EMRE form the channel while Ca 2+ -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 2+ conditions. A Ca 2+ -bound structure of MICU1-MICU2 at 3.1 Å resolution indicates how Ca 2+ -dependent changes enable dynamic response to cytosolic Ca 2+ signals.