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Mechanisms of EMRE-Dependent MCU Opening in the Mitochondrial Calcium Uniporter Complex
The mitochondrial calcium uniporter is a multi-subunit Ca(2+)-activated Ca(2+) channel, made up of the pore-forming MCU protein, a metazoan-specific EMRE subunit, and MICU1/MICU2, which mediate Ca(2+) activation. It has been established that metazoan MCU requires EMRE binding to conduct Ca(2+), but...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764451/ https://www.ncbi.nlm.nih.gov/pubmed/33296646 http://dx.doi.org/10.1016/j.celrep.2020.108486 |
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author | Van Keuren, Anna M. Tsai, Chen-Wei Balderas, Enrique Rodriguez, Madison X. Chaudhuri, Dipayan Tsai, Ming-Feng |
author_facet | Van Keuren, Anna M. Tsai, Chen-Wei Balderas, Enrique Rodriguez, Madison X. Chaudhuri, Dipayan Tsai, Ming-Feng |
author_sort | Van Keuren, Anna M. |
collection | PubMed |
description | The mitochondrial calcium uniporter is a multi-subunit Ca(2+)-activated Ca(2+) channel, made up of the pore-forming MCU protein, a metazoan-specific EMRE subunit, and MICU1/MICU2, which mediate Ca(2+) activation. It has been established that metazoan MCU requires EMRE binding to conduct Ca(2+), but how EMRE promotes MCU opening remains unclear. Here, we demonstrate that EMRE controls MCU activity via its transmembrane helix, while using an N-terminal PKP motif to strengthen binding with MCU. Opening of MCU requires hydrophobic interactions mediated by MCU residues near the pore’s luminal end. Enhancing these interactions by single mutation allows human MCU to transport Ca(2+) without EMRE. We further show that EMRE may facilitate MCU opening by stabilizing the open state in a conserved MCU gating mechanism, present also in non-metazoan MCU homologs. These results provide insights into the evolution of the uniporter machinery and elucidate the mechanism underlying the physiologically crucial EMRE-dependent MCU activation process. |
format | Online Article Text |
id | pubmed-7764451 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
record_format | MEDLINE/PubMed |
spelling | pubmed-77644512020-12-26 Mechanisms of EMRE-Dependent MCU Opening in the Mitochondrial Calcium Uniporter Complex Van Keuren, Anna M. Tsai, Chen-Wei Balderas, Enrique Rodriguez, Madison X. Chaudhuri, Dipayan Tsai, Ming-Feng Cell Rep Article The mitochondrial calcium uniporter is a multi-subunit Ca(2+)-activated Ca(2+) channel, made up of the pore-forming MCU protein, a metazoan-specific EMRE subunit, and MICU1/MICU2, which mediate Ca(2+) activation. It has been established that metazoan MCU requires EMRE binding to conduct Ca(2+), but how EMRE promotes MCU opening remains unclear. Here, we demonstrate that EMRE controls MCU activity via its transmembrane helix, while using an N-terminal PKP motif to strengthen binding with MCU. Opening of MCU requires hydrophobic interactions mediated by MCU residues near the pore’s luminal end. Enhancing these interactions by single mutation allows human MCU to transport Ca(2+) without EMRE. We further show that EMRE may facilitate MCU opening by stabilizing the open state in a conserved MCU gating mechanism, present also in non-metazoan MCU homologs. These results provide insights into the evolution of the uniporter machinery and elucidate the mechanism underlying the physiologically crucial EMRE-dependent MCU activation process. 2020-12-08 /pmc/articles/PMC7764451/ /pubmed/33296646 http://dx.doi.org/10.1016/j.celrep.2020.108486 Text en This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Van Keuren, Anna M. Tsai, Chen-Wei Balderas, Enrique Rodriguez, Madison X. Chaudhuri, Dipayan Tsai, Ming-Feng Mechanisms of EMRE-Dependent MCU Opening in the Mitochondrial Calcium Uniporter Complex |
title | Mechanisms of EMRE-Dependent MCU Opening in the Mitochondrial Calcium Uniporter Complex |
title_full | Mechanisms of EMRE-Dependent MCU Opening in the Mitochondrial Calcium Uniporter Complex |
title_fullStr | Mechanisms of EMRE-Dependent MCU Opening in the Mitochondrial Calcium Uniporter Complex |
title_full_unstemmed | Mechanisms of EMRE-Dependent MCU Opening in the Mitochondrial Calcium Uniporter Complex |
title_short | Mechanisms of EMRE-Dependent MCU Opening in the Mitochondrial Calcium Uniporter Complex |
title_sort | mechanisms of emre-dependent mcu opening in the mitochondrial calcium uniporter complex |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764451/ https://www.ncbi.nlm.nih.gov/pubmed/33296646 http://dx.doi.org/10.1016/j.celrep.2020.108486 |
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