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Journal of Molecular Biology Nov 2013Desmosomes are dynamic junctions between cells that maintain the structural integrity of skin and heart tissues by withstanding shear forces. Mutations in component... (Review)
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.
Topics: Animals; Desmoplakins; Desmosomes; Genetic Predisposition to Disease; Humans; Mutation; Plakophilins; Protein Binding; Protein Interaction Domains and Motifs
PubMed: 23911551
DOI: 10.1016/j.jmb.2013.07.035 -
Cell Communication & Adhesion Jun 2014The importance of desmosomes in tissue homeostasis is highlighted by natural and engineered mutations in desmosomal genes, which compromise the skin or heart and in some... (Review)
Review
The importance of desmosomes in tissue homeostasis is highlighted by natural and engineered mutations in desmosomal genes, which compromise the skin or heart and in some instances both. Desmosomal gene mutations account for 45-50% of cases of arrhythmogenic right ventricular cardiomyopathy, and are mutated in an array of other disorders such as striate palmoplantar keratoderma, hypotrichosis with or without skin vesicles and lethal acantholytic epidermolysis bullosa. Recently, we reported loss-of-function mutations in the human ADAM17 gene, encoding for the 'sheddase' ADAM17, a transmembrane protein which cleaves extracellular domains of substrate proteins including TNF-α, growth factors and desmoglein (DSG) 2. Patients present with cardiomyopathy and an inflammatory skin and bowel syndrome with defective DSG processing. In contrast, the dominantly inherited tylosis with oesophageal cancer appears to result from gain-of-function in ADAM17 due to increased processing via iRHOM2. This review discusses the heterogeneity of mutations in desmosomes and their regulatory proteins.
Topics: ADAM Proteins; ADAM17 Protein; Desmoplakins; Desmosomes; Humans; LEOPARD Syndrome; Mutation; Skin Diseases
PubMed: 24738885
DOI: 10.3109/15419061.2014.908854 -
Circulation Research Sep 2010Intercellular communication is essential for proper cardiac function. Mechanical and electrical activity need to be synchronized so that the work of individual myocytes... (Review)
Review
Intercellular communication is essential for proper cardiac function. Mechanical and electrical activity need to be synchronized so that the work of individual myocytes transforms into the pumping function of the organ. Mechanical continuity is provided by desmosomes and adherens junctions, while gap junctions provide a pathway for passage of ions and small molecules between cells. These complexes preferentially reside at the site of end-end contact between myocytes, within the intercalated disc. Recognition that some forms of arrhythmogenic cardiomyopathy are caused by mutations in desmosomal protein genes has galvanized interest in the biology of the desmosome and its interactions with other junctional molecules. This review presents the cellular and molecular biology of the desmosome, current knowledge on the relation of desmosomal mutations and disease phenotypes, and an overview of the molecular pathophysiology of arrhythmogenic right ventricular cardiomyopathy. Clinical experience and results from cellular and animal models provide insights into the intercalated disc as a functional unit and into the basic substrates that underlie pathogenesis and arrhythmogenesis of arrhythmogenic right ventricular cardiomyopathy.
Topics: Animals; Arrhythmias, Cardiac; Arrhythmogenic Right Ventricular Dysplasia; Desmosomes; Gap Junctions; Humans; Mutation
PubMed: 20847325
DOI: 10.1161/CIRCRESAHA.110.223412 -
Proceedings of the National Academy of... Nov 2020Desmosomes are cell-cell junctions that link tissue cells experiencing intense mechanical stress. Although the structure of the desmosomal cadherins is known, the...
Desmosomes are cell-cell junctions that link tissue cells experiencing intense mechanical stress. Although the structure of the desmosomal cadherins is known, the desmosome architecture-which is essential for mediating numerous functions-remains elusive. Here, we recorded cryo-electron tomograms (cryo-ET) in which individual cadherins can be discerned; they appear variable in shape, spacing, and tilt with respect to the membrane. The resulting sub-tomogram average reaches a resolution of ∼26 Å, limited by the inherent flexibility of desmosomes. To address this challenge typical of dynamic biological assemblies, we combine sub-tomogram averaging with atomistic molecular dynamics (MD) simulations. We generate models of possible cadherin arrangements and perform an in silico screening according to biophysical and structural properties extracted from MD simulation trajectories. We find a truss-like arrangement of cadherins that resembles the characteristic footprint seen in the electron micrograph. The resulting model of the desmosomal architecture explains their unique biophysical properties and strength.
Topics: Cadherins; Desmosomes; Electron Microscope Tomography; Humans; Intercellular Junctions; Molecular Dynamics Simulation
PubMed: 33067392
DOI: 10.1073/pnas.2004563117 -
Methods in Molecular Biology (Clifton,... 2021Desmosomes are cell-cell junctions responsible for mechanically integrating adjacent cells. Due to the small size of the junctions, their protein architecture cannot be...
Desmosomes are cell-cell junctions responsible for mechanically integrating adjacent cells. Due to the small size of the junctions, their protein architecture cannot be elucidated using conventional fluorescence microscopy. Super-resolution microscopy techniques, including dSTORM, deliver higher-resolution images which can reveal the localization or arrangement of proteins within individual desmosomes. Herein we describe an imaging and analysis method to determine the nanoscale architecture of desmosomes using super-resolution dSTORM.
Topics: Desmosomes; Microscopy, Fluorescence; Proteins
PubMed: 33225407
DOI: 10.1007/7651_2020_325 -
Journal of Cell Science Jan 2023Desmosome diseases are caused by dysfunction of desmosomes, which anchor intermediate filaments (IFs) at sites of cell-cell adhesion. For many decades, the focus of...
Desmosome diseases are caused by dysfunction of desmosomes, which anchor intermediate filaments (IFs) at sites of cell-cell adhesion. For many decades, the focus of attention has been on the role of actin filament-associated adherens junctions in development and disease, especially cancer. However, interference with the function of desmosomes, their molecular constituents or their attachments to IFs has now emerged as a major contributor to a variety of diseases affecting different tissues and organs including skin, heart and the digestive tract. The first Alpine desmosome disease meeting (ADDM) held in Grainau, Germany, in October 2022 brought together international researchers from the basic sciences with clinical experts from diverse fields to share and discuss their ideas and concepts on desmosome function and dysfunction in the different cell types involved in desmosome diseases. Besides the prototypic desmosomal diseases pemphigus and arrhythmogenic cardiomyopathy, the role of desmosome dysfunction in inflammatory bowel diseases and eosinophilic esophagitis was discussed.
Topics: Humans; Cell Adhesion; Desmosomes; Pemphigus; Disease
PubMed: 36594662
DOI: 10.1242/jcs.260832 -
Pediatric Cardiology Aug 2012Most commonly, arrhythmogenic cardiomyopathy (also known as arrhythmogenic right ventricular cardiomyopathy, or ARVC) is caused by mutations in desmosomal proteins. The... (Review)
Review
Most commonly, arrhythmogenic cardiomyopathy (also known as arrhythmogenic right ventricular cardiomyopathy, or ARVC) is caused by mutations in desmosomal proteins. The question arises as to the mechanisms by which mutations in mechanical junctions, affect the rhythm of the heart. We have proposed that a component of the arrhythmogenic substrate may include changes in the function of both, gap junctions and sodium channels. Here, we review the relevant literature on this subject.
Topics: Arrhythmogenic Right Ventricular Dysplasia; Desmosomes; Gap Junctions; Humans; Mutation; Sodium Channels
PubMed: 22407454
DOI: 10.1007/s00246-012-0257-0 -
Clinical and Experimental Dermatology Nov 2002In skin, desmosomes constitute critical adhesion complexes between adjacent keratinocytes that help maintain an intact epidermis. However, individual keratinocytes need... (Review)
Review
In skin, desmosomes constitute critical adhesion complexes between adjacent keratinocytes that help maintain an intact epidermis. However, individual keratinocytes need to migrate and differentiate and therefore desmosomes must have an inherent dynamic capacity to assemble and disassemble. This review highlights the role of the different structural junctional components involved in desmosome formation and turnover, as well as the possible signalling processes and pathways that may be implicated in desmosome homeostasis. Clues to the intricate nature of desmosome assembly and disassembly have been derived from human inherited and acquired blistering skin diseases as well as animal models and basic cell biology studies. The key implications for understanding desmosome dynamics from these findings are summarized in this review.
Topics: Blister; Calcium; Cell Adhesion; Darier Disease; Desmosomes; Humans; Intercellular Junctions; Keratinocytes; Pemphigus; Pemphigus, Benign Familial; Protein Kinase C; Structure-Activity Relationship
PubMed: 12472547
DOI: 10.1046/j.1365-2230.2002.01116.x -
Journal of Cell Science Mar 2006Human skin diseases have revealed fundamental mechanisms by which cytoskeletal proteins contribute to tissue architecture and function. In particular, the analysis of... (Review)
Review
Human skin diseases have revealed fundamental mechanisms by which cytoskeletal proteins contribute to tissue architecture and function. In particular, the analysis of epidermal blistering disorders and the role of keratin gene mutations in these diseases has led to significant increases in our understanding of intermediate filament biology. The major cell-surface attachment site for intermediate filament networks is the desmosome, an adhesive intercellular junction prominent in the epidermis and the heart. During the past decade, substantial progress has been made in understanding the molecular basis of a variety of epidermal autoimmune diseases, skin fragility syndromes, and disorders that involve a combination of heart and skin defects caused by perturbations in desmosome structure and function. These human diseases reveal key roles for desmosomes in maintaining tissue integrity, but also suggest functions for desmosomal components in signal transduction pathways and epidermal organization.
Topics: Cytoskeletal Proteins; Desmosomal Cadherins; Desmosomes; Humans; Skin Diseases
PubMed: 16495480
DOI: 10.1242/jcs.02888 -
Pathology Dec 2012Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an uncommon heart disease characterised by arrhythmias, right ventricular scarring, and fibrofatty change.... (Review)
Review
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an uncommon heart disease characterised by arrhythmias, right ventricular scarring, and fibrofatty change. Although mutations in the desmosome have been frequently observed in patients clinically diagnosed with ARVC, recent data have put a direct causal relationship in question. Many patients with ARVC and mutations have not had histological confirmation, and many family members with mutations are not affected. Desmosomal mutations have been found in other cardiac diseases, and the specificity of histopathological features is even in question. We aim to review the purported link between ARVC and the desmosome by a critical analysis of reported data.
Topics: Adolescent; Adult; Animals; Arrhythmogenic Right Ventricular Dysplasia; Desmosomes; Disease Models, Animal; Female; Humans; Male; Mice; Mutation; Plakophilins
PubMed: 23089739
DOI: 10.1097/PAT.0b013e32835a0163