Desmoplakin

Desmoplakin is a is_associated_with::protein in humans that is encoded by the DSP is_associated_with::gene. Desmoplakin is a critical component of is_associated_with::desmosome structures in is_associated_with::cardiac muscle and epidermal cells, which function to maintain the structural integrity at adjacent cell contacts. In is_associated_with::cardiac muscle, desmoplakin is localized to is_associated_with::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 is_associated_with::dilated cardiomyopathy, is_associated_with::arrhythmogenic right ventricular cardiomyopathy, is_associated_with::striate palmoplantar keratoderma, is_associated_with::Carvajal syndrome and is_associated_with::paraneoplastic pemphigus.

Structure
Desmoplakin exists as two predominant isoforms; the first, known as "DPII", has molecular weight 260.0 kDa (2272 amino acids) and the second, known as "DPI", has molecular weight 332.0 kDa (2871 amino acids). These is_associated_with::isoforms are identical except for the shorter rod domain in DPII. DPI is the predominant is_associated_with::isoform expressed in is_associated_with::cardiac muscle. The DSP gene is located on is_associated_with::chromosome 6p24.3, containing 24 is_associated_with::exons and spanning approximately 45 kDa of genomic is_associated_with::DNA. Desmoplakin is a large desmosomal plaque protein that is_associated_with::homodimerizes and adopts a dumbell-shaped conformation. The N-terminal globular head domain of desmoplakin is composed of a series of alpha helical bundles, and is required for both the localization to the desmosome and interaction with the N-terminal region of plakophilin 1 and plakoglobin. This is further sub divided into a region called the "Plakin domain" made up of six is_associated_with::spectrin repeat domains separated by is_associated_with::SH3 domain. A crystal structure of part of the plakin domain has been resolved, while the entire plakin domain has been elucidated using is_associated_with::small angle X-ray scattering which revealed a non-linear structure, an unexpected result considering is_associated_with::spectrin repeats are observed in linear orientations. The C-terminal region of desmoplakin is composed of three plakin repeat domains, termed A, B and C, which are essential for coalignment and binding of is_associated_with::intermediate filaments. Located at the most distal is_associated_with::C-terminus of desmoplakin is a region rich in is_associated_with::glycine–is_associated_with::serine–is_associated_with::arginine; it has been demonstrated that is_associated_with::serine is_associated_with::phosphorylation of this domain may modify desmoplakin-is_associated_with::intermediate filament interactions. In the mid-region of desmoplakin, a is_associated_with::coiled-coil rod domain is responsible for is_associated_with::homodimerization.

Function
Desmosomes are intercellular junctions that tightly link adjacent cells. Desmoplakin is an obligate component of functional desmosomes that anchors intermediate filaments to desmosomal plaques. In is_associated_with::cardiomyocytes, desmoplakin forms desmosomal plaques with the is_associated_with::intermediate filament desmin, whereas in is_associated_with::endothelial cells is_associated_with::cytokeratin type is_associated_with::intermediate filaments are recruited, and is_associated_with::vimentin in arachnoid and follicular dendritic cell types. Both types of is_associated_with::intermediate filaments attach in a lateral fashion to desmoplakin to form the plaque. In is_associated_with::cardiac muscle, desmoplakin is localized to is_associated_with::desmosomes in is_associated_with::intercalated discs. Desmoplakin isoform DPI is highly expressed and is thought to play a role in both the assembly and stabilization of is_associated_with::desmosomes; it's role is critical, as desmoplakin knockout mice display embryonic lethality. In mice overexpressing a C-terminal mutated desmoplakin protein, desmoplakin binding to desmin is disrupted in is_associated_with::cardiac muscle and hearts display abnormal is_associated_with::intercalated disc formation and structure. Much has been learned regarding desmoplakin function from mutations in patients with is_associated_with::arrhythmogenic right ventricular cardiomyopathy, where mutations in specific binding domains alter desmoplakin binding to is_associated_with::plakoglobin or desmin and result in cell death and dysfunction.

Clinical Significance
Mutations in this gene are the cause of several cardiomyopathies, including is_associated_with::dilated cardiomyopathy and is_associated_with::arrhythmogenic right ventricular cardiomyopathy. Mutations in DSP have also been associated with is_associated_with::striate palmoplantar keratoderma. is_associated_with::Carvajal syndrome results from an autosomal recessive mutation of a frameshift (7901delG) in DSP that results in a combination of above conditions, including is_associated_with::dilated cardiomyopathy, is_associated_with::keratoderma and is_associated_with::woolly hair. Patients with is_associated_with::Carvajal syndrome often suffer from is_associated_with::heart failure in teenage years. A case of compound heterozygosity for two DSP nonsense mutations resulting in is_associated_with::lethal acantholytic epidermolysis bullosa has been reported. Autoantibodies to DSP are a hallmark of the autoimmune disease is_associated_with::paraneoplastic pemphigus. Decreased desmoplakin expression has been found in patients with is_associated_with::oropharyngeal cancer and is_associated_with::breast cancer, which may alter cell-cell adhesion properties and propagate is_associated_with::metastasis.

Interactions
Desmoplakin has been shown to interact with:


 * is_associated_with::Desmin,
 * is_associated_with::Keratin 1,
 * is_associated_with::PKP1
 * is_associated_with::PKP2,
 * is_associated_with::Plakoglobin,  and
 * is_associated_with::Vimentin.