Desmocollins are a subfamily of desmosomal cadherins, the transmembrane constituents of desmosomes. [3] [4] They are co-expressed with desmogleins to link adjacent cells by extracellular adhesion. There are seven desmosomal cadherins in humans, three desmocollins and four desmogleins. [4] Desmosomal cadherins allow desmosomes to contribute to the integrity of tissue structure in multicellular living organisms. [5]
Three isoforms of desmocollin proteins have been identified. [6]
Each desmocollin gene encodes a pair of proteins: a longer 'a' form and a shorter 'b' form. The 'a' and 'b' forms differ in the length of their C-terminus tails. The protein pair is generated by alternative splicing. [4]
Desmocollin has four cadherin-like extracellular domains, an extracellular anchor domain, and an intracellular anchor domain. Additionally, the 'a' form has an intracellular cadherin-like sequence domain, which provides binding sites for other desmosomal proteins such as plakoglobin. [4]
The desmosomal cadherins are expressed in tissue-specific patterns. Desmocollin-2 and desmoglein-2 are found in all desmosome-containing tissues such as colon and cardiac muscle tissues, while other desmosomal cadherins are restricted to stratified epithelial tissues. [4]
All seven desmosomal cadherins are expressed in epidermis, but in a differentiation-specific manner. The '2' and '3' isoforms of desmocollin and desmoglein are expressed in the lower epidermal layers, and the '1' proteins and desmoglein-4 are expressed in the upper epidermal layers. Different isoforms are located in the same individual cells, and single desmosomes contain more than one isoform of both desmocollin and desmoglein. [4]
It is unclear why there are multiple desmosomal cadherin isoforms. It is thought that they may have different adhesive properties that are required at different levels in stratified epithelia or that they have specific functions in epithelial differentiation. [4]
Desmosomes are involved in cell-cell adhesion, and are particularly important for the integrity of heart and skin tissue. Because of this, desmocollin gene mutations can affect the adhesion of cells that undergo mechanical stress, notably cardiomyocytes and keratinocytes. Genetic disorders associated with desmocollin gene mutations include Carvajal syndrome, striate palmoplantar keratoderma, Naxos disease, and arrhythmogenic right ventricular cardiomyopathy. [7]
There is also evidence that autoimmunity against desmosomal cadherins contributes to cardiac inflammation associated with arrhythmogenic right ventricular cardiomyopathy, and that anti-desmosomal cadherin antibodies may represent new therapeutic targets. [8]
Intermediate filaments (IFs) are cytoskeletal structural components found in the cells of vertebrates, and many invertebrates. Homologues of the IF protein have been noted in an invertebrate, the cephalochordate Branchiostoma.
Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indirect interaction, where cells attach to surrounding extracellular matrix, a gel-like structure containing molecules released by cells into spaces between them. Cells adhesion occurs from the interactions between cell-adhesion molecules (CAMs), transmembrane proteins located on the cell surface. Cell adhesion links cells in different ways and can be involved in signal transduction for cells to detect and respond to changes in the surroundings. Other cellular processes regulated by cell adhesion include cell migration and tissue development in multicellular organisms. Alterations in cell adhesion can disrupt important cellular processes and lead to a variety of diseases, including cancer and arthritis. Cell adhesion is also essential for infectious organisms, such as bacteria or viruses, to cause diseases.
A desmosome, also known as a macula adherens, is a cell structure specialized for cell-to-cell adhesion. A type of junctional complex, they are localized spot-like adhesions randomly arranged on the lateral sides of plasma membranes. Desmosomes are one of the stronger cell-to-cell adhesion types and are found in tissue that experience intense mechanical stress, such as cardiac muscle tissue, bladder tissue, gastrointestinal mucosa, and epithelia.
Arrhythmogenic cardiomyopathy (ACM), arrhythmogenic right ventricular dysplasia (ARVD), or arrhythmogenic right ventricular cardiomyopathy (ARVC), most commonly is an inherited heart disease.
Hemidesmosomes are very small stud-like structures found in keratinocytes of the epidermis of skin that attach to the extracellular matrix. They are similar in form to desmosomes when visualized by electron microscopy, however, desmosomes attach to adjacent cells. Hemidesmosomes are also comparable to focal adhesions, as they both attach cells to the extracellular matrix. Instead of desmogleins and desmocollins in the extracellular space, hemidesmosomes utilize integrins. Hemidesmosomes are found in epithelial cells connecting the basal epithelial cells to the lamina lucida, which is part of the basal lamina. Hemidesmosomes are also involved in signaling pathways, such as keratinocyte migration or carcinoma cell intrusion.
Cadherins (named for "calcium-dependent adhesion") are cell adhesion molecules important in forming adherens junctions that let cells adhere to each other. Cadherins are a class of type-1 transmembrane proteins, and they depend on calcium (Ca2+) ions to function, hence their name. Cell-cell adhesion is mediated by extracellular cadherin domains, whereas the intracellular cytoplasmic tail associates with numerous adaptors and signaling proteins, collectively referred to as the cadherin adhesome.
The desmogleins are a family of desmosomal cadherins consisting of proteins DSG1, DSG2, DSG3, and DSG4. They play a role in the formation of desmosomes that join cells to one another.
Desmoglein-1 is a protein that in humans is encoded by the DSG1 gene. Desmoglein-1 is expressed everywhere in the skin epidermis, but mainly it is expressed in the superficial upper layers of the skin epidermis.
Desmoglein-3 is a protein that in humans is encoded by the DSG3 gene. In the skin epidermis Desmoglein-3 is expressed in the basal lower layers of the epidermis, and dominates in terms of expression on mucosal surfaces compared to Desmoglein-1.
Desmoglein-2 is a protein that in humans is encoded by the DSG2 gene. Desmoglein-2 is highly expressed in epithelial cells and cardiomyocytes. Desmoglein-2 is localized to desmosome structures at regions of cell-cell contact and functions to structurally adhere adjacent cells together. In cardiac muscle, these regions are specialized regions known as intercalated discs. Mutations in desmoglein-2 have been associated with arrhythmogenic right ventricular cardiomyopathy and familial dilated cardiomyopathy.
Desmoplakin is a protein in humans that is encoded by the DSP gene. Desmoplakin is a critical component of desmosome structures in cardiac muscle and epidermal cells, which function to maintain the structural integrity at adjacent cell contacts. In cardiac muscle, desmoplakin is localized to intercalated discs which mechanically couple cardiac cells to function in a coordinated syncytial structure. Mutations in desmoplakin have been shown to play a role in dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy, where it may present with acute myocardial injury; striate palmoplantar keratoderma, Carvajal syndrome and paraneoplastic pemphigus.
Plakoglobin, also known as junction plakoglobin or gamma-catenin, is a protein that in humans is encoded by the JUP gene. Plakoglobin is a member of the catenin protein family and homologous to β-catenin. Plakoglobin is a cytoplasmic component of desmosomes and adherens junctions structures located within intercalated discs of cardiac muscle that function to anchor sarcomeres and join adjacent cells in cardiac muscle. Mutations in plakoglobin are associated with arrhythmogenic right ventricular dysplasia.
Cadherin-2 also known as Neural cadherin (N-cadherin), is a protein that in humans is encoded by the CDH2 gene. CDH2 has also been designated as CD325 . Cadherin-2 is a transmembrane protein expressed in multiple tissues and functions to mediate cell–cell adhesion. In cardiac muscle, Cadherin-2 is an integral component in adherens junctions residing at intercalated discs, which function to mechanically and electrically couple adjacent cardiomyocytes. Alterations in expression and integrity of Cadherin-2 has been observed in various forms of disease, including human dilated cardiomyopathy. Variants in CDH2 have also been identified to cause a syndromic neurodevelopmental disorder.
Desmocollin-2 is a protein that in humans is encoded by the DSC2 gene. Desmocollin-2 is a cadherin-type protein that functions to link adjacent cells together in specialized regions known as desmosomes. Desmocollin-2 is widely expressed, and is the only desmocollin isoform expressed in cardiac muscle, where it localizes to intercalated discs. Mutations in DSC2 have been causally linked to arrhythmogenic right ventricular cardiomyopathy.
Desmocollin-1 is a protein that in humans is encoded by the DSC1 gene.
Plakophilin-1 is a protein that in humans is encoded by the PKP1 gene.
Desmocollin-3 is a protein that in humans is encoded by the DSC3 gene.
Plakophilin-2 is a protein that in humans is encoded by the PKP2 gene. Plakophilin 2 is expressed in skin and cardiac muscle, where it functions to link cadherins to intermediate filaments in the cytoskeleton. In cardiac muscle, plakophilin-2 is found in desmosome structures located within intercalated discs. Mutations in PKP2 have been shown to be causal in arrhythmogenic right ventricular cardiomyopathy.
Naxos disease is a cutaneous condition characterized by a palmoplantar keratoderma. The prevalence of the syndrome is up to 1 in every 1000 people in the Greek islands.
Cell–cell interaction refers to the direct interactions between cell surfaces that play a crucial role in the development and function of multicellular organisms. These interactions allow cells to communicate with each other in response to changes in their microenvironment. This ability to send and receive signals is essential for the survival of the cell. Interactions between cells can be stable such as those made through cell junctions. These junctions are involved in the communication and organization of cells within a particular tissue. Others are transient or temporary such as those between cells of the immune system or the interactions involved in tissue inflammation. These types of intercellular interactions are distinguished from other types such as those between cells and the extracellular matrix. The loss of communication between cells can result in uncontrollable cell growth and cancer.