Plectin is a giant protein found in nearly all mammaliancells which acts as a link between the three main components of the cytoskeleton: actin microfilaments, microtubules and intermediate filaments.[5] In addition plectin links the cytoskeleton to junctions found in the plasma membrane that structurally connect different cells. By holding these different networks together plectin plays an important role in maintaining the mechanical integrity and viscoelastic properties of tissues.[6]
Structure
Plectin can exist in cells as several alternatively-spliced isoforms, all around 500 kDa and >4000 amino acids.[7][8] The structure of plectin is thought to be a dimer consisting of a central coiled coil of 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 cytokeratin and vimentin. At the opposite end of the protein, in the N-terminal domain, a region has been defined as responsible for binding to actin.[9] In 2004, the exact crystal structure of this actin-binding domain (ABD) was determined in mice and shown to be composed of two calponin homology (CH) domains.[10] Plectin is expressed in nearly all mammalian tissues. In cardiac muscle and skeletal muscle, plectin is localized to specialized entities known as Z-discs.[11] Plectin binds several proteins, including vinculin, DES,[12]actin.,[6][13] fodrin,[6][13] microtubule-associating proteins,[6][13] nuclear laminin B.,[6][13]SPTAN1,[14][15]vimentin[14][15][16] and ITGB4.[6][13]
Function
Studies employing a plectin 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 keratinocytes. Skeletal and cardiac muscle tissues were also significantly affected. Cardiac 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 vinculin in muscle cells was strikingly down-regulated.[17]
Through the use of gold-immunoelectron microscopy, immunoblotting and 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,[12] 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 sarcomere.[18] Plectin also functions to link cytoskeleton to intercellular junctions, such as desmosomes and 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, desmoplakin and intermediate filaments.[19] In hemidesmosomes plectin has been shown to interact with the integrin β4 subunits of the hemidesmosome plaque and function in a clamp-like manner to link the intermediate filament cytokeratin to the junction.[20]
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.[21]
Plectin has been proposed as a biomarker for pancreatic cancer.[22][23] Although normally a cytoplasmic protein, plectin is expressed on the cell membrane in pancreatic ductal adenocarcinoma (PDAC) and can therefore be used to target PDAC cells.[22]
^Winter L, Wiche G (Jan 2013). "The many faces of plectin and plectinopathies: pathology and mechanisms". Acta Neuropathologica. 125 (1): 77–93. doi:10.1007/s00401-012-1026-0. PMID22864774.
^Sevcík J, Urbániková L, Kost'an J, Janda L, Wiche G (May 2004). "Actin-binding domain of mouse plectin. Crystal structure and binding to vimentin". European Journal of Biochemistry / FEBS. 271 (10): 1873–84. doi:10.1111/j.1432-1033.2004.04095.x. PMID15128297.
^Zernig G, Wiche G (Jul 1985). "Morphological integrity of single adult cardiac myocytes isolated by collagenase treatment: immunolocalization of tubulin, microtubule-associated proteins 1 and 2, plectin, vimentin, and vinculin". European Journal of Cell Biology. 38 (1): 113–22. PMID2992982.
^ abHijikata T, Murakami T, Imamura M, Fujimaki N, Ishikawa H (Mar 1999). "Plectin is a linker of intermediate filaments to Z-discs in skeletal muscle fibers". Journal of Cell Science. 112 (6): 867–76. PMID10036236.
^ abHerrmann H, Wiche G (Jan 1987). "Plectin and IFAP-300K are homologous proteins binding to microtubule-associated proteins 1 and 2 and to the 240-kilodalton subunit of spectrin". The Journal of Biological Chemistry. 262 (3): 1320–5. PMID3027087.
^ abBrown MJ, Hallam JA, Liu Y, Yamada KM, Shaw S (Jul 2001). "Cutting edge: integration of human T lymphocyte cytoskeleton by the cytolinker plectin". Journal of Immunology. 167 (2): 641–5. doi:10.4049/jimmunol.167.2.641. PMID11441066.
^Favre B, Schneider Y, Lingasamy P, Bouameur JE, Begré N, Gontier Y, Steiner-Champliaud MF, Frias MA, Borradori L, Fontao L (May 2011). "Plectin interacts with the rod domain of type III intermediate filament proteins desmin and vimentin". European Journal of Cell Biology. 90 (5): 390–400. doi:10.1016/j.ejcb.2010.11.013. PMID21296452.
^Andrä K, Lassmann H, Bittner R, Shorny S, Fässler R, Propst F, Wiche G (Dec 1997). "Targeted inactivation of plectin reveals essential function in maintaining the integrity of skin, muscle, and heart cytoarchitecture". Genes & Development. 11 (23): 3143–56. doi:10.1101/gad.11.23.3143. PMID9389647.
^Reipert S, Steinböck F, Fischer I, Bittner RE, Zeöld A, Wiche G (Nov 1999). "Association of mitochondria with plectin and desmin intermediate filaments in striated muscle". Experimental Cell Research. 252 (2): 479–91. doi:10.1006/excr.1999.4626. PMID10527638.
^Huber O (Sep 2003). "Structure and function of desmosomal proteins and their role in development and disease". Cellular and Molecular Life Sciences. 60 (9): 1872–90. doi:10.1007/s00018-003-3050-7. PMID14523549.
Herrmann H, Wiche G (Jan 1987). "Plectin and IFAP-300K are homologous proteins binding to microtubule-associated proteins 1 and 2 and to the 240-kilodalton subunit of spectrin". The Journal of Biological Chemistry. 262 (3): 1320–5. PMID3027087.
Malecz N, Foisner R, Stadler C, Wiche G (Apr 1996). "Identification of plectin as a substrate of p34cdc2 kinase and mapping of a single phosphorylation site". The Journal of Biological Chemistry. 271 (14): 8203–8. doi:10.1074/jbc.271.14.8203. PMID8626512.{{cite journal}}: CS1 maint: unflagged free DOI (link)
Henzler T, Harmache A, Herrmann H, Spring H, Suzan M, Audoly G, Panek T, Bosch V (Mar 2001). "Fully functional, naturally occurring and C-terminally truncated variant human immunodeficiency virus (HIV) Vif does not bind to HIV Gag but influences intermediate filament structure". The Journal of General Virology. 82 (Pt 3): 561–73. doi:10.1099/0022-1317-82-3-561. PMID11172097.
Nakano A, Pulkkinen L, Murrell D, Rico J, Lucky AW, Garzon M, Stevens CA, Robertson S, Pfendner E, Uitto J (May 2001). "Epidermolysis bullosa with congenital pyloric atresia: novel mutations in the beta 4 integrin gene (ITGB4) and genotype/phenotype correlations". Pediatric Research. 49 (5): 618–26. doi:10.1203/00006450-200105000-00003. PMID11328943.
Brown MJ, Hallam JA, Liu Y, Yamada KM, Shaw S (Jul 2001). "Cutting edge: integration of human T lymphocyte cytoskeleton by the cytolinker plectin". Journal of Immunology. 167 (2): 641–5. doi:10.4049/jimmunol.167.2.641. PMID11441066.
Koss-Harnes D, Høyheim B, Anton-Lamprecht I, Gjesti A, Jørgensen RS, Jahnsen FL, Olaisen B, Wiche G, Gedde-Dahl T (Jan 2002). "A site-specific plectin mutation causes dominant epidermolysis bullosa simplex Ogna: two identical de novo mutations". The Journal of Investigative Dermatology. 118 (1): 87–93. doi:10.1046/j.0022-202x.2001.01591.x. PMID11851880.
