Structural insights into the Ca2+-dependent gating of the human mitochondrial calcium uniporter
- University of Texas Southwestern Medical Center, United States
- Massachusetts General Hospital, United States
Abstract
Mitochondrial Ca2+ uptake is mediated by an inner mitochondrial membrane protein called the mitochondrial calcium uniporter. In humans, the uniporter functions as a holocomplex consisting of MCU, EMRE, MICU1 and MICU2, among which MCU and EMRE form a subcomplex and function as the conductive channel while MICU1 and MICU2 are EF-hand proteins that regulate the channel activity in a Ca2+ dependent manner. Here we present the EM structures of the human mitochondrial calcium uniporter holocomplex (uniplex) in the presence and absence of Ca2+, revealing distinct Ca2+ dependent assembly of the uniplex. Our structural observations suggest that Ca2+ changes the dimerization interaction between MICU1 and MICU2, which in turn determines how the MICU1-MICU2 subcomplex interacts with the MCU-EMRE channel and, consequently, changes the distribution of the uniplex assemblies between the blocked and unblocked states.
Data availability
The cryo-EM density maps of the human MCU-EMRE-MICU1-MICU2 holocomplex have been deposited in the Electron Microscopy Data Bank under accession numbers EMD-22215 for the Ca2+-bound state, EMD- 22216 for the apo, blocked state, EMD-22213 for the apo, bridging state and EMD-22214 for the apo, competing state. Atomic coordinates have been deposited in the Protein Data Bank under accession numbers 6XJV for the Ca2+-bound state and 6XJX for the apo, blocked state.
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Atomic coordinates for the Ca2+-bound stateProtein Data Bank, 6XJV.
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Atomic coordinates for the apo, blocked stateProtein Data Bank, 6XJX.
Article and author information
Author details
Funding
Howard Hughes Medical Institute
- Youxing Jiang
Howard Hughes Medical Institute
- Vamsi K Mootha
National Institute of General Medical Sciences (GM079179)
- Youxing Jiang
National Institute of General Medical Sciences (GM136976)
- Xiao-chen Bai
Welch Foundation (I-1578)
- Youxing Jiang
Welch Foundation (I-1944)
- Xiao-chen Bai
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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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Structural insights into the Ca2+-dependent gating of the human mitochondrial calcium uniporter
eLife 9:e60513.
https://doi.org/10.7554/eLife.60513
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