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

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Data availability
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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).

The following data sets were generated

1. Wang C
2. Jacewicz A
3. Delgado BD
4. Baradaran R
5. Long SB
(2020) holocomplex in low Ca2+
EMDB, EMD-22290.

http://www.ebi.ac.uk/pdbe/entry/emdb/EMD-22290
1. Wang C
2. Jacewicz A
3. Delgado BD
4. Baradaran R
5. Long SB
(2020) holocomplex in low Ca2+
Protein Data Bank, 6XQN.

http://www.rcsb.org/structure/6XQN
1. Wang C
2. Jacewicz A
3. Delgado BD
4. Baradaran R
5. Long SB
(2020) Ca2+-bound MICU1-MICU2 heterodimer
EMDB, EMD-22291.

http://www.ebi.ac.uk/pdbe/entry/emdb/EMD-22291
1. Wang C
2. Jacewicz A
3. Delgado BD
4. Baradaran R
5. Long SB
(2020) Ca2+-bound MICU1-MICU2 heterodimer
Protein Data Bank, 6XQO.

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

Article and author information

Author details

Chongyuan Wang

Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States

Competing interests
The authors declare that no competing interests exist.
Agata Jacewicz

Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States

Competing interests
The authors declare that no competing interests exist.
Bryce D Delgado

Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States

Competing interests
The authors declare that no competing interests exist.
Rozbeh Baradaran

Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States

Competing interests
The authors declare that no competing interests exist.
Stephen Barstow Long

Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States

For correspondence
longs@mskcc.org

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8144-1398

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.

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.