Plectin Explained

Plectin is a giant protein found in nearly all mammalian cells which acts as a link between the three main components of the cytoskeleton: actin microfilaments, microtubules and intermediate filaments.[1] 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.[2]

Structure

Plectin can exist in cells as several alternatively-spliced isoforms, all around 500 kDa and >4000 amino acids.[3] [4] 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.[5] 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.[6] Plectin is expressed in nearly all mammalian tissues. In cardiac muscle and skeletal muscle, plectin is localized to specialized entities known as Z-discs.[7] Plectin binds several proteins, including vinculin, DES,[8] actin,[9] fodrin, microtubule-associating proteins, nuclear laminin B, SPTAN1,[10] [11] vimentin[10] [11] [12] and ITGB4.[2] [9]

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.[13] 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,[8] 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 facilitate the close association of myofibrils and mitochondria, both at Z-discs and along the remainder the sarcomere.[14] 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.[15] 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.[16]

Clinical significance

Mutations in PLEC have been associated with epidermolysis bullosa simplex with muscular dystrophy.[17] A missense variant of PLEC has been recently proposed as a cause of atrial fibrillation in some populations.[18] Isolated left ventricular non-compaction accompanying epidermolysis bullosa simplex with muscular dystrophy was also noted.[19] Plectin has been proposed as a biomarker for pancreatic cancer.[20] [21] 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.

See also

Further reading

External links

Notes and References

  1. Svitkina TM, Verkhovsky AB, Borisy GG . Plectin sidearms mediate interaction of intermediate filaments with microtubules and other components of the cytoskeleton . The Journal of Cell Biology . 135 . 4 . 991–1007 . Nov 1996 . 8922382 . 2133373 . 10.1083/jcb.135.4.991 .
  2. Wiche G . Role of plectin in cytoskeleton organization and dynamics . Journal of Cell Science . 111 . 17 . 2477–86 . Sep 1998 . 10.1242/jcs.111.17.2477 . 9701547 . abstract .
  3. Web site: Plectin in: Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) . dead . https://web.archive.org/web/20160305222654/http://heartproteome.org/copa/proteininfo.aspx?qtype=protein%20id&qvalue=q15149-2 . 2016-03-05 . 2015-04-13.
  4. Zong . Nobel C. . Li . Haomin . Li . Hua . Lam . Maggie P.Y. . Jimenez . Rafael C. . Kim . Christina S. . Deng . Ning . Kim . Allen K. . Choi . Jeong Ho . Zelaya . Ivette . Liem . David . Meyer . David . Odeberg . Jacob . Fang . Caiyun . Lu . Hao-jie . 2013-10-12 . Integration of Cardiac Proteome Biology and Medicine by a Specialized Knowledgebase . Circulation Research . en . 113 . 9 . 1043–1053 . 10.1161/CIRCRESAHA.113.301151 . 0009-7330 . 4076475 . 23965338.
  5. Winter L, Wiche G . The many faces of plectin and plectinopathies: pathology and mechanisms . Acta Neuropathologica . 125 . 1 . Jan 2013 . 22864774 . 10.1007/s00401-012-1026-0 . 77–93. 12429741 .
  6. Sevcík J, Urbániková L, Kost'an J, Janda L, Wiche G . Actin-binding domain of mouse plectin. Crystal structure and binding to vimentin . European Journal of Biochemistry . 271 . 10 . 1873–84 . May 2004 . 15128297 . 10.1111/j.1432-1033.2004.04095.x . free .
  7. Zernig G, Wiche G . 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 . Jul 1985 . 2992982 . 113–22.
  8. Hijikata T, Murakami T, Imamura M, Fujimaki N, Ishikawa H . Plectin is a linker of intermediate filaments to Z-discs in skeletal muscle fibers . Journal of Cell Science . 112 . Mar 1999 . 10036236 . 6 . 867–76. 10.1242/jcs.112.6.867 .
  9. Steinböck FA, Wiche G . Plectin: a cytolinker by design . Biological Chemistry . 380 . 2 . Feb 1999 . 10195422 . 10.1515/BC.1999.023 . 151–8. 46726381 . free .
  10. Herrmann H, Wiche G . 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 . Jan 1987 . 10.1016/S0021-9258(19)75789-5 . 3027087 . free .
  11. Brown MJ, Hallam JA, Liu Y, Yamada KM, Shaw S . Cutting edge: integration of human T lymphocyte cytoskeleton by the cytolinker plectin . Journal of Immunology . 167 . 2 . 641–5 . Jul 2001 . 11441066 . 10.4049/jimmunol.167.2.641 . free .
  12. Favre B, Schneider Y, Lingasamy P, Bouameur JE, Begré N, Gontier Y, Steiner-Champliaud MF, Frias MA, Borradori L, Fontao L . Plectin interacts with the rod domain of type III intermediate filament proteins desmin and vimentin . European Journal of Cell Biology . 90 . 5 . May 2011 . 21296452 . 10.1016/j.ejcb.2010.11.013 . 390–400.
  13. Andrä K, Lassmann H, Bittner R, Shorny S, Fässler R, Propst F, Wiche G . Targeted inactivation of plectin reveals essential function in maintaining the integrity of skin, muscle, and heart cytoarchitecture . Genes & Development . 11 . 23 . Dec 1997 . 9389647 . 3143–56 . 10.1101/gad.11.23.3143 . 316746.
  14. Reipert S, Steinböck F, Fischer I, Bittner RE, Zeöld A, Wiche G . Association of mitochondria with plectin and desmin intermediate filaments in striated muscle . Experimental Cell Research . 252 . 2 . Nov 1999 . 10527638 . 10.1006/excr.1999.4626 . 479–91.
  15. Huber O . Structure and function of desmosomal proteins and their role in development and disease . Cellular and Molecular Life Sciences . 60 . 9 . Sep 2003 . 14523549 . 10.1007/s00018-003-3050-7 . 1872–90. 11557417 . 11138567 .
  16. Sonnenberg A, Liem RK . Plakins in development and disease . Experimental Cell Research . 313 . 10 . Jun 2007 . 17499243 . 10.1016/j.yexcr.2007.03.039 . 2189–203.
  17. Bardhan. Ajoy. Bruckner-Tuderman. Leena. Chapple. Iain L. C.. Fine. Jo-David. Harper. Natasha. Has. Cristina. Magin. Thomas M.. Marinkovich. M. Peter. Marshall. John F.. McGrath. John A.. Mellerio. Jemima E.. 2020-09-24. Epidermolysis bullosa. Nature Reviews Disease Primers. en. 6. 1. 78. 10.1038/s41572-020-0210-0. 32973163. 221861310. 2056-676X.
  18. A Missense Variant in PLEC Increases Risk of Atrial Fibrillation. 10.1016/j.jacc.2017.09.005. 29050564. 5704994. Journal of the American College of Cardiology. 70. 17. 2157–2168. 2017. Thorolfsdottir. Rosa B.. Sveinbjornsson. Gardar. Sulem. Patrick. Helgadottir. Anna. Gretarsdottir. Solveig. Benonisdottir. Stefania. Magnusdottir. Audur. Davidsson. Olafur B.. Rajamani. Sridharan. Roden. Dan M.. Darbar. Dawood. Pedersen. Terje R.. Sabatine. Marc S.. Jonsdottir. Ingileif. Arnar. David O.. Thorsteinsdottir. Unnur. Gudbjartsson. Daniel F.. Holm. Hilma. Stefansson. Kari.
  19. Villa CR, Ryan TD, Collins JJ, Taylor MD, Lucky AW, Jefferies JL . Left ventricular non-compaction cardiomyopathy associated with epidermolysis bullosa simplex with muscular dystrophy and PLEC1 mutation . Neuromuscular Disorders . 25 . 2 . Feb 2015 . 25454730 . 10.1016/j.nmd.2014.09.011 . 165–8. 25193440 .
  20. Kelly KA, Bardeesy N, Anbazhagan R, Gurumurthy S, Berger J, Alencar H, Depinho RA, Mahmood U, Weissleder R . Targeted nanoparticles for imaging incipient pancreatic ductal adenocarcinoma . PLOS Medicine . 5 . 4 . e85 . Apr 2008 . 18416599 . 2292750 . 10.1371/journal.pmed.0050085 . free .
  21. Bausch D, Thomas S, Mino-Kenudson M, Fernández-del CC, Bauer TW, Williams M, Warshaw AL, Thayer SP, Kelly KA . Plectin-1 as a novel biomarker for pancreatic cancer . Clinical Cancer Research . 17 . 2 . 302–9 . Jan 2011 . 21098698 . 3044444 . 10.1158/1078-0432.CCR-10-0999 .
  22. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P . Integration of cardiac proteome biology and medicine by a specialized knowledgebase . Circulation Research . 113 . 9 . Oct 2013 . 23965338 . 10.1161/CIRCRESAHA.113.301151 . 4076475 . 1043–1053.