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

The mitochondrial calcium uniporter is a Ca2+-gated ion channel complex that controls mitochondrial Ca2+ entry and regulates cell metabolism. MCU and EMRE form the channel while Ca2+-dependent regulation is conferred by MICU1 and MICU2 through an enigmatic process. We present a cryo-EM structure of...

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Bibliographic Details
Published in:eLife 2020-07, Vol.9
Main Authors: Wang, Chongyuan, Jacewicz, Agata, Delgado, Bryce D, Baradaran, Rozbeh, Long, Stephen Barstow
Format: Article
Language:English
Subjects:
Biochemistry and Chemical Biology
Calcium (mitochondrial)
calcium channel
Calcium influx
Calcium signalling
Data collection
gating
ion channel
Lipids
membrane structure
Mitochondria
Proteins
Software
Structural Biology and Molecular Biophysics
toxin
tribolium castaneum
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Summary:The mitochondrial calcium uniporter is a Ca2+-gated ion channel complex that controls mitochondrial Ca2+ entry and regulates cell metabolism. MCU and EMRE form the channel while Ca2+-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 Ca2+ conditions. A Ca2+-bound structure of MICU1-MICU2 at 3.1 Å resolution indicates how Ca2+-dependent changes enable dynamic response to cytosolic Ca2+ signals.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.59991