Plectin

Plectin is a giant is_associated_with::protein found in nearly all is_associated_with::mammalian cells which acts as a link between the three main components of the is_associated_with::cytoskeleton: is_associated_with::actin microfilaments, is_associated_with::microtubules and is_associated_with::intermediate filaments. In addition plectin links the cytoskeleton to junctions found in the is_associated_with::plasma membrane that structurally connect different cells. By holding these different networks together plectin plays an important role in maintaining the mechanical integrity and is_associated_with::viscoelastic properties of tissues.

Structure
Plectin can exist in cells as several alternatively-spliced isoforms, all around 500 kDa and >4000 amino acids. The structure of plectin is thought to be a dimer consisting of a central is_associated_with::coiled coil of is_associated_with::alpha helices connecting two large globular domains (one at each terminus). These globular domains are responsible for connecting plectin to its various cytoskeletal targets. The carboxy-terminal domain is made of 6 highly homologous repeating regions. The subdomain between regions five and six of this domain is known to connect to the intermediate filaments is_associated_with::cytokeratin and is_associated_with::vimentin. At the opposite end of the protein, in the N-terminal domain, a region has been defined as responsible for binding to is_associated_with::actin. In 2004, the exact crystal structure of this is_associated_with::actin-binding domain (ABD) was determined in mice and shown to be composed of two is_associated_with::calponin homology (CH) domains. Plectin is expressed in nearly all mammalian tissues. In is_associated_with::cardiac muscle and is_associated_with::skeletal muscle, plectin is localized to specialized entities known as Z-discs. Plectin binds several proteins, including is_associated_with::vinculin, is_associated_with::DES, is_associated_with::actin., fodrin,  microtubule-associating proteins,  nuclear laminin B.,  is_associated_with::SPTAN1,  vimentin  and is_associated_with::ITGB4.

Function
Studies employing a plectin is_associated_with::knockout mouse have shed light on the functions of plectin. Pups died 2–3 days after birth, and these mice exhibited marked skin abnormalities, including degeneration of is_associated_with::keratinocytes. Skeletal and cardiac muscle tissues were also significantly affected. Cardiac is_associated_with::intercalated discs were disintegrated and sarcomeres were irregularly shapen, and intracellular accumulation of aberrant isolated myofibrillar bundles and Z-disc components was also observed. Expression of is_associated_with::vinculin in muscle cells was strikingly down-regulated. Through the use of gold-immunoelectron microscopy, is_associated_with::immunoblotting and is_associated_with::immunofluorescence experiments plectin has been found to associate with all three major components of the cytoskeleton. In muscle, plectin binds to the periphery of Z-discs, and along with the intermediate filament protein desmin, may form lateral linkages among neighboring Z-discs. This interaction between plectin and desmin intermediate filaments also appears to faclitate the close association of myofibrils and mitochondria, both at Z-discs and along the remainder the is_associated_with::sarcomere. Plectin also functions to link cytoskeleton to intercellular junctions, such as is_associated_with::desmosomes and is_associated_with::hemidesmosomes, which link intermediate filament networks between cells. Plectin has been revealed to localize to the desmosomes and in vitro studies have shown that it can form bridges between the desmosome protein, is_associated_with::desmoplakin and intermediate filaments. In hemidesmosomes plectin has been shown to interact with the is_associated_with::integrin β4 subunits of the hemidesmosome plaque and function in a clamp like manner to crosslink the intermediate filament, is_associated_with::cytokeratin to the junction.

Clinical Significance
Mutations in PLEC have been associated with epidermolysis bullosa simplex with muscular dystrophy. Isolated left ventricular non-compaction accompanying epidermolysis bullosa simplex with muscular dystrophy was also noted. Plectin has been proposed as a is_associated_with::biomarker for is_associated_with::pancreatic cancer. Although normally a is_associated_with::cytoplasmic protein, plectin is expressed on the cell membrane in pancreatic ductal adenocarcinoma (PDAC) and can therefore be used to target PDAC cells.