01 November 2013
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
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.