Structures reveal gatekeeping of the mitochondrial Ca2+ uniporter by MICU1-MICU2
- Memorial Sloan Kettering Cancer Center, United States
Abstract
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.
Data availability
The atomic coordinates and EM maps have been deposited in the Protein Data Bank (www.rcsb.org) and the EMDB (www.ebi.ac.uk/pdbe/emdb/): PDB ID 6XQN, EMDB ID EMD-22290 (holocomplex in low Ca2+); PDB ID 6XQO, EMDB ID EMD-22291 (Ca2+-bound MICU1-MICU2 heterodimer).
Article and author information
Author details
Stephen Barstow Long
Funding
National Institute of General Medical Sciences (R35GM131921)
- Stephen Barstow Long
National Cancer Institute (P30CA008748)
- Stephen Barstow Long
National Institute of General Medical Sciences (5T32GM008539)
- Bryce D Delgado
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Kenton J Swartz, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States
Version history
- Received: June 13, 2020
- Accepted: July 14, 2020
- Accepted Manuscript published: July 15, 2020 (version 1)
- Accepted Manuscript updated: July 23, 2020 (version 2)
- Version of Record published: August 18, 2020 (version 3)
Copyright
© 2020, Wang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Structures reveal gatekeeping of the mitochondrial Ca2+ uniporter by MICU1-MICU2
eLife 9:e59991.
https://doi.org/10.7554/eLife.59991
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