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Mechanistic Basis of Desmosome-Targeted Diseases

Desmosomes are dynamic junctions between cells that maintain the structural integrity of skin and heart tissues by withstanding shear forces. Mutations in component genes cause life-threatening conditions including arrhythmogenic right ventricular cardiomyopathy, and desmosomal proteins are targeted...

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Detalles Bibliográficos
Autores principales: Al-Jassar, Caezar, Bikker, Hennie, Overduin, Michael, Chidgey, Martyn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3807649/
https://www.ncbi.nlm.nih.gov/pubmed/23911551
http://dx.doi.org/10.1016/j.jmb.2013.07.035
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author Al-Jassar, Caezar
Bikker, Hennie
Overduin, Michael
Chidgey, Martyn
author_facet Al-Jassar, Caezar
Bikker, Hennie
Overduin, Michael
Chidgey, Martyn
author_sort Al-Jassar, Caezar
collection PubMed
description Desmosomes are dynamic junctions between cells that maintain the structural integrity of skin and heart tissues by withstanding shear forces. Mutations in component genes cause life-threatening conditions including arrhythmogenic right ventricular cardiomyopathy, and desmosomal proteins are targeted by pathogenic autoantibodies in skin blistering diseases such as pemphigus. Here, we review a set of newly discovered pathogenic alterations and discuss the structural repercussions of debilitating mutations on desmosomal proteins. The architectures of native desmosomal assemblies have been visualized by cryo-electron microscopy and cryo-electron tomography, and the network of protein domain interactions is becoming apparent. Plakophilin and desmoplakin mutations have been discovered to alter binding interfaces, structures, and stabilities of folded domains that have been resolved by X-ray crystallography and NMR spectroscopy. The flexibility within desmoplakin has been revealed by small-angle X-ray scattering and fluorescence assays, explaining how mechanical stresses are accommodated. These studies have shown that the structural and functional consequences of desmosomal mutations can now begin to be understood at multiple levels of spatial and temporal resolution. This review discusses the recent structural insights and raises the possibility of using modeling for mechanism-based diagnosis of how deleterious mutations alter the integrity of solid tissues.
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spelling pubmed-38076492013-11-01 Mechanistic Basis of Desmosome-Targeted Diseases Al-Jassar, Caezar Bikker, Hennie Overduin, Michael Chidgey, Martyn J Mol Biol Review Desmosomes are dynamic junctions between cells that maintain the structural integrity of skin and heart tissues by withstanding shear forces. Mutations in component genes cause life-threatening conditions including arrhythmogenic right ventricular cardiomyopathy, and desmosomal proteins are targeted by pathogenic autoantibodies in skin blistering diseases such as pemphigus. Here, we review a set of newly discovered pathogenic alterations and discuss the structural repercussions of debilitating mutations on desmosomal proteins. The architectures of native desmosomal assemblies have been visualized by cryo-electron microscopy and cryo-electron tomography, and the network of protein domain interactions is becoming apparent. Plakophilin and desmoplakin mutations have been discovered to alter binding interfaces, structures, and stabilities of folded domains that have been resolved by X-ray crystallography and NMR spectroscopy. The flexibility within desmoplakin has been revealed by small-angle X-ray scattering and fluorescence assays, explaining how mechanical stresses are accommodated. These studies have shown that the structural and functional consequences of desmosomal mutations can now begin to be understood at multiple levels of spatial and temporal resolution. This review discusses the recent structural insights and raises the possibility of using modeling for mechanism-based diagnosis of how deleterious mutations alter the integrity of solid tissues. Elsevier 2013-11-01 /pmc/articles/PMC3807649/ /pubmed/23911551 http://dx.doi.org/10.1016/j.jmb.2013.07.035 Text en © 2013 The Authors https://creativecommons.org/licenses/by-nc-nd/3.0/ Open Access under CC BY-NC-ND 3.0 (https://creativecommons.org/licenses/by-nc-nd/3.0/) license
spellingShingle Review
Al-Jassar, Caezar
Bikker, Hennie
Overduin, Michael
Chidgey, Martyn
Mechanistic Basis of Desmosome-Targeted Diseases
title Mechanistic Basis of Desmosome-Targeted Diseases
title_full Mechanistic Basis of Desmosome-Targeted Diseases
title_fullStr Mechanistic Basis of Desmosome-Targeted Diseases
title_full_unstemmed Mechanistic Basis of Desmosome-Targeted Diseases
title_short Mechanistic Basis of Desmosome-Targeted Diseases
title_sort mechanistic basis of desmosome-targeted diseases
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3807649/
https://www.ncbi.nlm.nih.gov/pubmed/23911551
http://dx.doi.org/10.1016/j.jmb.2013.07.035
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