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Misfolding of mutant adenine nucleotide translocase in yeast supports a novel mechanism of Ant1-induced muscle diseases

Approximately one-third of proteins in the cell reside in the membrane. Mutations in membrane proteins can induce conformational changes and expose nonnative polar domains/residues to the lipid environment. The molecular effect of the resulting membrane stress is poorly defined. Adenine nucleotide t...

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Autores principales: Liu, Yaxin, Wang, Xiaowen, Chen, Xin Jie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472010/
https://www.ncbi.nlm.nih.gov/pubmed/25833713
http://dx.doi.org/10.1091/mbc.E15-01-0030
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author Liu, Yaxin
Wang, Xiaowen
Chen, Xin Jie
author_facet Liu, Yaxin
Wang, Xiaowen
Chen, Xin Jie
author_sort Liu, Yaxin
collection PubMed
description Approximately one-third of proteins in the cell reside in the membrane. Mutations in membrane proteins can induce conformational changes and expose nonnative polar domains/residues to the lipid environment. The molecular effect of the resulting membrane stress is poorly defined. Adenine nucleotide translocase 1 (Ant1) is a mitochondrial inner membrane protein involved in ATP/ADP exchange. Missense mutations in the Ant1 isoform cause autosomal dominant progressive external ophthalmoplegia (adPEO), cardiomyopathy, and myopathy. The mechanism of the Ant1-induced pathologies is highly debated. Here we show that equivalent mutations in the yeast Aac2 protein cause protein misfolding. Misfolded Aac2 drastically affects the assembly and stability of multiple protein complexes in the membrane, which ultimately inhibits cell growth. Despite causing similar proteostatic damages, the adPEO- but not the cardiomyopathy/myopathy-type Aac2 proteins form large aggregates. The data suggest that the Ant1-induced diseases belong to protein misfolding disorders. Protein homeostasis is subtly maintained on the mitochondrial inner membrane and can be derailed by the misfolding of one single protein with or without aggregate formation. This finding could have broad implications for understanding other dominant diseases (e.g., retinitis pigmentosa) caused by missense mutations in membrane proteins.
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spelling pubmed-44720102015-08-16 Misfolding of mutant adenine nucleotide translocase in yeast supports a novel mechanism of Ant1-induced muscle diseases Liu, Yaxin Wang, Xiaowen Chen, Xin Jie Mol Biol Cell Articles Approximately one-third of proteins in the cell reside in the membrane. Mutations in membrane proteins can induce conformational changes and expose nonnative polar domains/residues to the lipid environment. The molecular effect of the resulting membrane stress is poorly defined. Adenine nucleotide translocase 1 (Ant1) is a mitochondrial inner membrane protein involved in ATP/ADP exchange. Missense mutations in the Ant1 isoform cause autosomal dominant progressive external ophthalmoplegia (adPEO), cardiomyopathy, and myopathy. The mechanism of the Ant1-induced pathologies is highly debated. Here we show that equivalent mutations in the yeast Aac2 protein cause protein misfolding. Misfolded Aac2 drastically affects the assembly and stability of multiple protein complexes in the membrane, which ultimately inhibits cell growth. Despite causing similar proteostatic damages, the adPEO- but not the cardiomyopathy/myopathy-type Aac2 proteins form large aggregates. The data suggest that the Ant1-induced diseases belong to protein misfolding disorders. Protein homeostasis is subtly maintained on the mitochondrial inner membrane and can be derailed by the misfolding of one single protein with or without aggregate formation. This finding could have broad implications for understanding other dominant diseases (e.g., retinitis pigmentosa) caused by missense mutations in membrane proteins. The American Society for Cell Biology 2015-06-01 /pmc/articles/PMC4472010/ /pubmed/25833713 http://dx.doi.org/10.1091/mbc.E15-01-0030 Text en © 2015 Liu et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Liu, Yaxin
Wang, Xiaowen
Chen, Xin Jie
Misfolding of mutant adenine nucleotide translocase in yeast supports a novel mechanism of Ant1-induced muscle diseases
title Misfolding of mutant adenine nucleotide translocase in yeast supports a novel mechanism of Ant1-induced muscle diseases
title_full Misfolding of mutant adenine nucleotide translocase in yeast supports a novel mechanism of Ant1-induced muscle diseases
title_fullStr Misfolding of mutant adenine nucleotide translocase in yeast supports a novel mechanism of Ant1-induced muscle diseases
title_full_unstemmed Misfolding of mutant adenine nucleotide translocase in yeast supports a novel mechanism of Ant1-induced muscle diseases
title_short Misfolding of mutant adenine nucleotide translocase in yeast supports a novel mechanism of Ant1-induced muscle diseases
title_sort misfolding of mutant adenine nucleotide translocase in yeast supports a novel mechanism of ant1-induced muscle diseases
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472010/
https://www.ncbi.nlm.nih.gov/pubmed/25833713
http://dx.doi.org/10.1091/mbc.E15-01-0030
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AT chenxinjie misfoldingofmutantadeninenucleotidetranslocaseinyeastsupportsanovelmechanismofant1inducedmusclediseases