Calcium uptake protein 2, mitochondrial
uniplex complex
Structures reveal gatekeeping of the mitochondrial Ca<sup>2+</sup> uniporter by MICU1-MICU2.
The mitochondrial calcium uniporter is a Ca<sup>2+</sup>-gated ion channel complex that controls mitochondrial Ca<sup>2+</sup> entry and regulates cell metabolism. MCU and EMRE form the channel while Ca<sup>2+</sup>-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<sup>2+</sup> conditions. A Ca<sup>2+</sup>-bound structure of MICU1-MICU2 at 3.1 Å resolution indicates how Ca<sup>2+</sup>-dependent changes enable dynamic response to cytosolic Ca<sup>2+</sup> signals.