CD81 explained

CD81 molecule, also known as CD81 (Cluster of Differentiation 81), is a protein which in humans is encoded by the CD81 gene.[1] [2] It is also known as 26 kDa cell surface protein, TAPA-1 (Target of the Antiproliferative Antibody 1), and Tetraspanin-28 (Tspan-28).

Gene

The gene is located on the plus strand of the short arm of chromosome 11 (11p15.5). It is 20,103 bases in length and encodes a protein of 236 amino acids (predicted molecular weight 25.809 kDa).[2]

The protein does not appear to be post translationally modified and has four transmembrane domains. Both the N-terminus and C-terminus lie on the intracellular side of the membrane.

The gene is expressed in hemopoietic, endothelial, and epithelial cells. It is absent from erythrocytes, platelets, and neutrophils.

Function

The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is a cell surface glycoprotein that is known to complex with integrins. This protein appears to promote muscle cell fusion and support myotube maintenance. Also it may be involved in signal transduction. This gene is localized in the tumor-suppressor gene region and thus it is a candidate gene for malignancies.[1]

The tetraspanin family includes CD9, CD37, CD53, CD63, CD81 (this protein), CD82 and CD151.

CD81 interacts directly with immunoglobulin superfamily member 8 (IGSF8,[3] CD316) and CD36. It forms a signal transduction complex with CD19, CD21 and Leu-13 (CD225) on the surface of the B cell.[4] On T cells CD81 associates with CD4 and CD8 and provides a costimulatory signal with CD3.

Clinical significance

This protein plays a critical role in Hepatitis C attachment and/or cell entry by interacting with virus' E1/E2 glycoproteins heterodimer.[5] The large extracellular loop of CD81 binds the hepatitis E2 glycoprotein dimer. HCV-E2 and CD81 binding Kd is 1.8 nM. HCV-E2 engaged CD81 is only 30% internalized after 12hr, suggesting CD81 may be primarily an attachment receptor for HCV.[6]

It also appears to play a role in liver invasion by Plasmodium species.[7] CD81 is required for Plasmodium vivax sporozoite entry into human hepatocytes and for Plasmodium yoelii sporozoite entry into murine hepatocytes.[8]

HIV gag proteins use tetraspanin enriched microdomains (containing minimally CD81, CD82, CD63) as a platform for virion assembly and release. Purified HIV produced by MOLT\HIV cells contains CD81. Anti-CD81 antibodies downregulate HIV production 3 fold, however the CD81 protein free virus is more infectious.[9] Engagement of CD81 lowers the signaling threshold required to trigger T-Cell\CD3 mediated proviral DNA in CD4+ T cells.[10]

CD81 appears to play a role in the pathogenesis of influenza.[11]

Interactions

CD81 has been shown to interact with TSPAN4,[12] CD19,[13] [14] [15] CD9,[15] [16] PTGFRN,[17] [18] CD117[19] and CD29.[20] [21]

Ligands

Benzyl salicylate[22] and terfenadine[23] have been shown to bind to CD81.

See also

Further reading

Notes and References

  1. Web site: Entrez Gene: CD81 CD81 molecule.
  2. Andria ML, Hsieh CL, Oren R, Francke U, Levy S . Genomic organization and chromosomal localization of the TAPA-1 gene . Journal of Immunology . 147 . 3 . 1030–6 . August 1991 . 10.4049/jimmunol.147.3.1030 . 1650385 . 31032048 .
  3. Clark K.L. . Zeng Z. . Langford A.L. . Bowen S.M. . Todd S.C. . PGRL is a major CD81-associated protein on lymphocytes and distinguishes a new family of cell surface proteins . Journal of Immunology . 167 . 9 . 5115–5121 . November 2001 . 11673522 . 10.4049/jimmunol.167.9.5115. free .
  4. CD81 (TAPA-1): a molecule involved in signal transduction and cell adhesion in the immune system.. Annu Rev Immunol . 9597125. 10.1146/annurev.immunol.16.1.89. 16. 1998. 89–109. Levy S, Todd SC, Maecker HT .
  5. Bartosch B, Vitelli A, Granier C, Goujon C, Dubuisson J, Pascale S, Scarselli E, Cortese R, Nicosia A, Cosset FL . Cell entry of hepatitis C virus requires a set of co-receptors that include the CD81 tetraspanin and the SR-B1 scavenger receptor . The Journal of Biological Chemistry . 278 . 43 . 41624–30 . October 2003 . 12913001 . 10.1074/jbc.M305289200 . free .
  6. Petracca R, Falugi F, Galli G, Norais N, Rosa D, Campagnoli S, Burgio V, Di Stasio E, Giardina B, Houghton M, Abrignani S, Grandi G . Structure-function analysis of hepatitis C virus envelope-CD81 binding . J. Virol. . 74 . 10 . 4824–30 . May 2000 . 10775621 . 112005 . 10.1128/jvi.74.10.4824-4830.2000.
  7. Yalaoui S, Zougbédé S, Charrin S, Silvie O, Arduise C, Farhati K, Boucheix C, Mazier D, Rubinstein E, Froissard P . Hepatocyte Permissiveness to Plasmodium Infection Is Conveyed by a Short and Structurally Conserved Region of the CD81 Large Extracellular Domain . PLOS Pathogens . 4 . 2 . e1000010 . February 2008 . 18389082 . 2279262 . 10.1371/journal.ppat.1000010 . free .
  8. Silvie O, Rubinstein E, Franetich JF, Prenant M, Belnoue E, Rénia L, Hannoun L, Eling W, Levy S, Boucheix C, Mazier D . Hepatocyte CD81 is required for Plasmodium falciparum and Plasmodium yoelii sporozoite infectivity . Nat. Med. . 9 . 1 . 93–6 . January 2003 . 12483205 . 10.1038/nm808 . 6290736 .
  9. Grigorov B, Attuil-Audenis V, Perugi F, Nedelec M, Watson S, Pique C, Darlix JL, Conjeaud H, Muriaux D . A role for CD81 on the late steps of HIV-1 replication in a chronically infected T cell line . Retrovirology . 6 . 28 . 2009 . 19284574 . 2657109 . 10.1186/1742-4690-6-28 . free .
  10. Tardif MR, Tremblay MJ . Tetraspanin CD81 provides a costimulatory signal resulting in increased human immunodeficiency virus type 1 gene expression in primary CD4+ T lymphocytes through NF-kappaB, NFAT, and AP-1 transduction pathways . J. Virol. . 79 . 7 . 4316–28 . April 2005 . 15767432 . 1061526 . 10.1128/JVI.79.7.4316-4328.2005 .
  11. He J, Sun E, Bujny MV, Kim D, Davidson MW, Zhuang X . Dual Function of CD81 in Influenza Virus Uncoating and Budding . PLOS Pathog. . 9 . 10 . e1003701 . October 2013 . 24130495 . 10.1371/journal.ppat.1003701 . 3795033 . free .
  12. Tachibana I, Bodorova J, Berditchevski F, Zutter MM, Hemler ME . NAG-2, a novel transmembrane-4 superfamily (TM4SF) protein that complexes with integrins and other TM4SF proteins . J. Biol. Chem. . 272 . 46 . 29181–9 . Nov 1997 . 9360996 . 10.1074/jbc.272.46.29181 . free .
  13. Bradbury LE, Kansas GS, Levy S, Evans RL, Tedder TF . The CD19/CD21 signal transducing complex of human B lymphocytes includes the target of antiproliferative antibody-1 and Leu-13 molecules . J. Immunol. . 149 . 9 . 2841–50 . Nov 1992 . 10.4049/jimmunol.149.9.2841 . 1383329 . 23655762 . free .
  14. Imai T, Kakizaki M, Nishimura M, Yoshie O . Molecular analyses of the association of CD4 with two members of the transmembrane 4 superfamily, CD81 and CD82 . J. Immunol. . 155 . 3 . 1229–39 . Aug 1995 . 10.4049/jimmunol.155.3.1229 . 7636191 . 32942467 .
  15. Horváth G, Serru V, Clay D, Billard M, Boucheix C, Rubinstein E . CD19 is linked to the integrin-associated tetraspans CD9, CD81, and CD82 . J. Biol. Chem. . 273 . 46 . 30537–43 . Nov 1998 . 9804823 . 10.1074/jbc.273.46.30537 . free .
  16. Radford KJ, Thorne RF, Hersey P . CD63 associates with transmembrane 4 superfamily members, CD9 and CD81, and with beta 1 integrins in human melanoma . Biochem. Biophys. Res. Commun. . 222 . 1 . 13–8 . May 1996 . 8630057 . 10.1006/bbrc.1996.0690 .
  17. Charrin S, Le Naour F, Oualid M, Billard M, Faure G, Hanash SM, Boucheix C, Rubinstein E . The major CD9 and CD81 molecular partner. Identification and characterization of the complexes . J. Biol. Chem. . 276 . 17 . 14329–37 . Apr 2001 . 11278880 . 10.1074/jbc.M011297200 . free .
  18. Stipp CS, Orlicky D, Hemler ME . FPRP, a major, highly stoichiometric, highly specific CD81- and CD9-associated protein . J. Biol. Chem. . 276 . 7 . 4853–62 . Feb 2001 . 11087758 . 10.1074/jbc.M009859200 . free .
  19. Anzai N . Lee Younghee . Youn Byung-S . Fukuda Seiji . Kim Young-June . Mantel Charlie . Akashi Makoto . Broxmeyer Hal E . C-kit associated with the transmembrane 4 superfamily proteins constitutes a functionally distinct subunit in human hematopoietic progenitors . Blood . 99 . 12 . 4413–21 . Jun 2002 . 12036870 . 10.1182/blood.V99.12.4413 .
  20. Serru V, Le Naour F, Billard M, Azorsa DO, Lanza F, Boucheix C, Rubinstein E . Selective tetraspan-integrin complexes (CD81/alpha4beta1, CD151/alpha3beta1, CD151/alpha6beta1) under conditions disrupting tetraspan interactions . Biochem. J. . 340 . Pt 1 . 103–11 . May 1999 . 10229664 . 1220227 . 10.1042/0264-6021:3400103 .
  21. Mazzocca A . Carloni Vinicio . Sciammetta Silvia . Cordella Claudia . Pantaleo Pietro . Caldini Anna . Gentilini Paolo . Pinzani Massimo . Expression of transmembrane 4 superfamily (TM4SF) proteins and their role in hepatic stellate cell motility and wound healing migration . J. Hepatol. . 37 . 3 . 322–30 . Sep 2002 . 12175627 . 10.1016/S0168-8278(02)00175-7 .
  22. Rajesh S, Sridhar P, Tews BA, Fénéant L, Cocquerel L, Ward DG, Berditchevski F, Overduin M . Structural basis of ligand interactions of the large extracellular domain of tetraspanin CD81 . J Virol . 86. 18. 9606–16. June 2012 . 22740401 . 10.1128/JVI.00559-12 . 3446547.
  23. Holzer M, Ziegler S, Albrecht B, Kronenberger B, Kaul A, Bartenschlager R, Kattner L, Klein CD, Hartmann RW . Identification of terfenadine as an inhibitor of human CD81-receptor HCV-E2 interaction: synthesis and structure optimization . Molecules . 13 . 5 . 1081–110 . 2008 . 18560330 . 6245452 . 10.3390/molecules13051081. free .

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