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Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis

[Image: see text] Advances over the past 25 years have revealed much about how the structural properties of membranes and associated proteins are linked to the thermodynamics and kinetics of membrane protein (MP) folding. At the same time biochemical progress has outlined how cellular proteostasis n...

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Autores principales: Marinko, Justin T., Huang, Hui, Penn, Wesley D., Capra, John A., Schlebach, Jonathan P., Sanders, Charles R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2019
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506414/
https://www.ncbi.nlm.nih.gov/pubmed/30608666
http://dx.doi.org/10.1021/acs.chemrev.8b00532
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author Marinko, Justin T.
Huang, Hui
Penn, Wesley D.
Capra, John A.
Schlebach, Jonathan P.
Sanders, Charles R.
author_facet Marinko, Justin T.
Huang, Hui
Penn, Wesley D.
Capra, John A.
Schlebach, Jonathan P.
Sanders, Charles R.
author_sort Marinko, Justin T.
collection PubMed
description [Image: see text] Advances over the past 25 years have revealed much about how the structural properties of membranes and associated proteins are linked to the thermodynamics and kinetics of membrane protein (MP) folding. At the same time biochemical progress has outlined how cellular proteostasis networks mediate MP folding and manage misfolding in the cell. When combined with results from genomic sequencing, these studies have established paradigms for how MP folding and misfolding are linked to the molecular etiologies of a variety of diseases. This emerging framework has paved the way for the development of a new class of small molecule “pharmacological chaperones” that bind to and stabilize misfolded MP variants, some of which are now in clinical use. In this review, we comprehensively outline current perspectives on the folding and misfolding of integral MPs as well as the mechanisms of cellular MP quality control. Based on these perspectives, we highlight new opportunities for innovations that bridge our molecular understanding of the energetics of MP folding with the nuanced complexity of biological systems. Given the many linkages between MP misfolding and human disease, we also examine some of the exciting opportunities to leverage these advances to address emerging challenges in the development of therapeutics and precision medicine.
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spelling pubmed-65064142019-05-13 Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis Marinko, Justin T. Huang, Hui Penn, Wesley D. Capra, John A. Schlebach, Jonathan P. Sanders, Charles R. Chem Rev [Image: see text] Advances over the past 25 years have revealed much about how the structural properties of membranes and associated proteins are linked to the thermodynamics and kinetics of membrane protein (MP) folding. At the same time biochemical progress has outlined how cellular proteostasis networks mediate MP folding and manage misfolding in the cell. When combined with results from genomic sequencing, these studies have established paradigms for how MP folding and misfolding are linked to the molecular etiologies of a variety of diseases. This emerging framework has paved the way for the development of a new class of small molecule “pharmacological chaperones” that bind to and stabilize misfolded MP variants, some of which are now in clinical use. In this review, we comprehensively outline current perspectives on the folding and misfolding of integral MPs as well as the mechanisms of cellular MP quality control. Based on these perspectives, we highlight new opportunities for innovations that bridge our molecular understanding of the energetics of MP folding with the nuanced complexity of biological systems. Given the many linkages between MP misfolding and human disease, we also examine some of the exciting opportunities to leverage these advances to address emerging challenges in the development of therapeutics and precision medicine. American Chemical Society 2019-01-04 2019-05-08 /pmc/articles/PMC6506414/ /pubmed/30608666 http://dx.doi.org/10.1021/acs.chemrev.8b00532 Text en Copyright © 2019 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Marinko, Justin T.
Huang, Hui
Penn, Wesley D.
Capra, John A.
Schlebach, Jonathan P.
Sanders, Charles R.
Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis
title Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis
title_full Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis
title_fullStr Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis
title_full_unstemmed Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis
title_short Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis
title_sort folding and misfolding of human membrane proteins in health and disease: from single molecules to cellular proteostasis
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506414/
https://www.ncbi.nlm.nih.gov/pubmed/30608666
http://dx.doi.org/10.1021/acs.chemrev.8b00532
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