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Mechanistic Basis of Desmosome-Targeted Diseases

1 , , 2 , 1 , * , 1

Journal of Molecular Biology

Elsevier

ARVC, arrhythmogenic right ventricular cardiomyopathy, DIFC, desmosome–intermediate filament complex, EC, extracellular cadherin, EGFR, epidermal growth factor receptor, IA, intracellular anchor, iPSC, induced pluripotent stem cell, ICS, intracellular cadherin-typical sequence, Lef, lymphoid enhancer factor, NMD, nonsense-mediated RNA decay, PPAR, peroxisome proliferator-activated receptor, PRD, plakin repeat domain, SR, spectrin repeat, SH3, Src homology 3, Tcf, T-cell factor, desmosomal cadherin, desmoplakin, desmosome, arrhythmogenic right ventricular cardiomyopathy, plakoglobin

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      Abstract

      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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        The WNT signal transduction cascade controls myriad biological phenomena throughout development and adult life of all animals. In parallel, aberrant Wnt signaling underlies a wide range of pathologies in humans. In this Review, we provide an update of the core Wnt/β-catenin signaling pathway, discuss how its various components contribute to disease, and pose outstanding questions to be addressed in the future. Copyright © 2012 Elsevier Inc. All rights reserved.
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          Cell signaling mechanisms often transmit information via posttranslational protein modifications, most importantly reversible protein phosphorylation. Here we develop and apply a general mass spectrometric technology for identification and quantitation of phosphorylation sites as a function of stimulus, time, and subcellular location. We have detected 6,600 phosphorylation sites on 2,244 proteins and have determined their temporal dynamics after stimulating HeLa cells with epidermal growth factor (EGF) and recorded them in the Phosida database. Fourteen percent of phosphorylation sites are modulated at least 2-fold by EGF, and these were classified by their temporal profiles. Surprisingly, a majority of proteins contain multiple phosphorylation sites showing different kinetics, suggesting that they serve as platforms for integrating signals. In addition to protein kinase cascades, the targets of reversible phosphorylation include ubiquitin ligases, guanine nucleotide exchange factors, and at least 46 different transcriptional regulators. The dynamic phosphoproteome provides a missing link in a global, integrative view of cellular regulation.
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            Author and article information

            Affiliations
            [1 ]School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK
            [2 ]Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands
            Author notes
            [* ]Corresponding author. m.overduin@ 123456bham.ac.uk
            [†]

            Present address: C. Al-Jassar, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.

            Contributors
            Journal
            J Mol Biol
            J. Mol. Biol
            Journal of Molecular Biology
            Elsevier
            0022-2836
            1089-8638
            01 November 2013
            01 November 2013
            : 425
            : 21
            : 4006-4022
            23911551
            3807649
            S0022-2836(13)00483-X
            10.1016/j.jmb.2013.07.035
            © 2013 The Authors

            This document may be redistributed and reused, subject to certain conditions.

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