Structural insights into the Ca2+-dependent gating of the human mitochondrial calcium uniporter

Abstract
Data availability
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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.

The following data sets were generated

1. Jiang Y
2. et al
(2020) human MCU-EMRE-MICU1-MICU2 holocomplex, Ca2+-bound state
EMD-22215.

http://www.ebi.ac.uk/pdbe/entry/emdb/EMD-22215
1. Jiang Y
2. et al
(2020) human MCU-EMRE-MICU1-MICU2 holocomplex, apo, blocked state
EMD- 22216.

http://www.ebi.ac.uk/pdbe/entry/emdb/EMD- 22216
1. Jiang Y
2. et al
(2020) human MCU-EMRE-MICU1-MICU2 holocomplex, apo, bridging state
EMD-22213.

http://www.ebi.ac.uk/pdbe/entry/emdb/EMD-22213
1. Jiang Y
2. et al
(2020) human MCU-EMRE-MICU1-MICU2 holocomplex, apo, competing state
EMD-22214.

http://www.ebi.ac.uk/pdbe/entry/emdb/EMD-22214
1. Jiang Y
2. et al
(2020) Atomic coordinates for the Ca2+-bound state
6XJV.

http://www.rcsb.org/structure/6XJV
1. Jiang Y
2. et al
(2020) Atomic coordinates for the apo, blocked state
6XJX.

http://www.rcsb.org/structure/6XJX

Article and author information

Author details

Yan Wang

Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Yan Han

Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Ji She

Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7006-6230
Nam X Nguyen

Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Vamsi K Mootha

Molecular Biology, Massachusetts General Hospital, Boston, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9924-642X
Xiao-chen Bai

Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4234-5686
Youxing Jiang

Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States

For correspondence
youxing.jiang@utsouthwestern.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1874-0504

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

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.