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

  1. Yan Wang
  2. Yan Han
  3. Ji She
  4. Nam X Nguyen
  5. Vamsi K Mootha
  6. Xiao-chen Bai
  7. Youxing Jiang  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
  2. 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.

The following data sets were generated

Article and author information

Author details

  1. Yan Wang

    Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Yan Han

    Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ji She

    Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7006-6230
  4. 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.
  5. Vamsi K Mootha

    Molecular Biology, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9924-642X
  6. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4234-5686
  7. 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.
    ORCID icon "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.

Reviewing Editor

  1. Kenton J Swartz, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States

Version history

  1. Received: June 28, 2020
  2. Accepted: August 6, 2020
  3. Accepted Manuscript published: August 7, 2020 (version 1)
  4. Accepted Manuscript updated: August 10, 2020 (version 2)
  5. Version of Record published: August 21, 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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  1. Yan Wang
  2. Yan Han
  3. Ji She
  4. Nam X Nguyen
  5. Vamsi K Mootha
  6. Xiao-chen Bai
  7. Youxing Jiang
(2020)
Structural insights into the Ca2+-dependent gating of the human mitochondrial calcium uniporter
eLife 9:e60513.
https://doi.org/10.7554/eLife.60513

Share this article

https://doi.org/10.7554/eLife.60513

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    This work was supported by the Weizmann Krenter Foundation and the Weizmann – Ichilov (Tel Aviv Sourasky Medical Center) Collaborative Grant in Biomedical Research, by the Minerva Foundation, by the ISF KillCorona grant 3777/19.