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Evolutionary divergence reveals the molecular basis of EMRE dependence of the human MCU

The mitochondrial calcium uniporter (MCU) is a calcium-activated calcium channel critical for signaling and bioenergetics. MCU, the pore-forming subunit of the uniporter, contains two transmembrane domains and is found in all major eukaryotic taxa. In amoeba and fungi, MCU homologs are sufficient to...

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Detalles Bibliográficos
Autores principales: MacEwen, Melissa JS, Markhard, Andrew L, Bozbeyoglu, Mert, Bradford, Forrest, Goldberger, Olga, Mootha, Vamsi K, Sancak, Yasemin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Life Science Alliance LLC 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425227/
https://www.ncbi.nlm.nih.gov/pubmed/32769116
http://dx.doi.org/10.26508/lsa.202000718
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author MacEwen, Melissa JS
Markhard, Andrew L
Bozbeyoglu, Mert
Bradford, Forrest
Goldberger, Olga
Mootha, Vamsi K
Sancak, Yasemin
author_facet MacEwen, Melissa JS
Markhard, Andrew L
Bozbeyoglu, Mert
Bradford, Forrest
Goldberger, Olga
Mootha, Vamsi K
Sancak, Yasemin
author_sort MacEwen, Melissa JS
collection PubMed
description The mitochondrial calcium uniporter (MCU) is a calcium-activated calcium channel critical for signaling and bioenergetics. MCU, the pore-forming subunit of the uniporter, contains two transmembrane domains and is found in all major eukaryotic taxa. In amoeba and fungi, MCU homologs are sufficient to form a functional calcium channel, whereas human MCU exhibits a strict requirement for the metazoan protein essential MCU regulator (EMRE) for conductance. Here, we exploit this evolutionary divergence to decipher the molecular basis of human MCU’s dependence on EMRE. By systematically generating chimeric proteins that consist of EMRE-independent Dictyostelium discoideum MCU and Homo sapiens MCU (HsMCU), we converged on a stretch of 10 amino acids in D. discoideum MCU that can be transplanted to HsMCU to render it EMRE independent. We call this region in human MCU the EMRE dependence domain (EDD). Crosslinking experiments show that EMRE directly interacts with HsMCU at its transmembrane domains as well as the EDD. Our results suggest that EMRE stabilizes the EDD of MCU, permitting both channel opening and calcium conductance, consistent with recently published structures of MCU-EMRE.
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spelling pubmed-74252272020-08-26 Evolutionary divergence reveals the molecular basis of EMRE dependence of the human MCU MacEwen, Melissa JS Markhard, Andrew L Bozbeyoglu, Mert Bradford, Forrest Goldberger, Olga Mootha, Vamsi K Sancak, Yasemin Life Sci Alliance Research Articles The mitochondrial calcium uniporter (MCU) is a calcium-activated calcium channel critical for signaling and bioenergetics. MCU, the pore-forming subunit of the uniporter, contains two transmembrane domains and is found in all major eukaryotic taxa. In amoeba and fungi, MCU homologs are sufficient to form a functional calcium channel, whereas human MCU exhibits a strict requirement for the metazoan protein essential MCU regulator (EMRE) for conductance. Here, we exploit this evolutionary divergence to decipher the molecular basis of human MCU’s dependence on EMRE. By systematically generating chimeric proteins that consist of EMRE-independent Dictyostelium discoideum MCU and Homo sapiens MCU (HsMCU), we converged on a stretch of 10 amino acids in D. discoideum MCU that can be transplanted to HsMCU to render it EMRE independent. We call this region in human MCU the EMRE dependence domain (EDD). Crosslinking experiments show that EMRE directly interacts with HsMCU at its transmembrane domains as well as the EDD. Our results suggest that EMRE stabilizes the EDD of MCU, permitting both channel opening and calcium conductance, consistent with recently published structures of MCU-EMRE. Life Science Alliance LLC 2020-08-07 /pmc/articles/PMC7425227/ /pubmed/32769116 http://dx.doi.org/10.26508/lsa.202000718 Text en © 2020 MacEwen et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Articles
MacEwen, Melissa JS
Markhard, Andrew L
Bozbeyoglu, Mert
Bradford, Forrest
Goldberger, Olga
Mootha, Vamsi K
Sancak, Yasemin
Evolutionary divergence reveals the molecular basis of EMRE dependence of the human MCU
title Evolutionary divergence reveals the molecular basis of EMRE dependence of the human MCU
title_full Evolutionary divergence reveals the molecular basis of EMRE dependence of the human MCU
title_fullStr Evolutionary divergence reveals the molecular basis of EMRE dependence of the human MCU
title_full_unstemmed Evolutionary divergence reveals the molecular basis of EMRE dependence of the human MCU
title_short Evolutionary divergence reveals the molecular basis of EMRE dependence of the human MCU
title_sort evolutionary divergence reveals the molecular basis of emre dependence of the human mcu
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425227/
https://www.ncbi.nlm.nih.gov/pubmed/32769116
http://dx.doi.org/10.26508/lsa.202000718
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