Biology:CD79A

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Cluster of differentiation CD79A also known as B-cell antigen receptor complex-associated protein alpha chain and MB-1 membrane glycoprotein, is a protein that in humans is encoded by the CD79A gene.[1]

The CD79a protein together with the related CD79b protein, forms a dimer associated with membrane-bound immunoglobulin in B-cells, thus forming the B-cell antigen receptor (BCR). This occurs in a similar manner to the association of CD3 with the T-cell receptor, and enables the cell to respond to the presence of antigens on its surface.[2]

It is associated with agammaglobulinemia-3.[3]

Gene

The mouse CD79A gene, then called mb-1, was cloned in the late 1980s,[4] followed by the discovery of human CD79A in the early 1990s.[5][6] It is a short gene, 4.3 kb in length, with 5 exons encoding for 2 splice variants resulting in 2 isoforms.[1]

CD79A is conserved and abundant among ray-finned fish (actinopterygii) but not in the evolutionarily more ancient chondrichthyes such as shark.[7] The occurrence of CD79A thus coincides with the evolution of B cell receptors with greater diversity generated by recombination of multiple V, D, and J elements in bony fish contrasting the single V, D and J elements found in shark.[8]

Structure

CD79a is a membrane protein with an extracellular immunoglobulin domain, a single span transmembrane region and a short cytoplasmic domain.[1] The cytoplasmic domain contains multiple phosphorylation sites including a conserved dual phosphotyrosine binding motif, termed immunotyrosine-based activation motif (ITAM).[9][10] The larger CD79a isoform contains an insert in position 88-127 of human CD79a resulting in a complete immunoglobulin domain, whereas the smaller isoform has only a truncated Ig-like domain.[1] CD79a has several cysteine residues, one of which forms covalent bonds with CD79b.[11]

Function

CD79a plays multiple and diverse roles in B cell development and function. The CD79a/b heterodimer associates non-covalently with the immunoglobulin heavy chain through its transmembrane region, thus forming the BCR along with the immunoglobulin light chain and the pre-BCR when associated with the surrogate light chain in developing B cells. Association of the CD79a/b heterodimer with the immunoglobulin heavy chain is required for surface expression of the BCR and BCR induced calcium flux and protein tyrosine phosphorylation.[12] Genetic deletion of the transmembrane exon of CD79A results in loss of CD79a protein and a complete block of B cell development at the pro to pre B cell transition.[13] Similarly, humans with homozygous splice variants in CD79A predicted to result in loss of the transmembrane region and a truncated or absent protein display agammaglobulinemia and no peripheral B cells.[3][14][15]

The CD79a ITAM tyrosines (human CD79a Tyr188 and Tyr199, mouse CD79a Tyr182 and Tyr193) phosphorylated in response to BCR crosslinking, are critical for binding of Src-homology 2 domain-containing kinases such as spleen tyrosine kinase (Syk) and signal transduction by CD79a.[16][17] In vivo, the CD79a ITAM tyrosines synergize with the CD79b ITAM tyrosines to mediate the transition from the pro to the pre B cell stage as suggested by the analysis of mice with targeted mutations of the CD79a and CD79b ITAM.[18][19] Loss of only one of the two functional CD79a/b ITAMs resulted in impaired B cell development but B cell functions such as the T cell independent type II response and BCR mediated calcium flux in the available B cells were intact. However, the presence of both the CD79a and CD79b ITAM tyrosines were required for normal T cell dependent antibody responses.[18][20] The CD79a cytoplasmic domain further contains a non-ITAM tyrosine distal of the CD79a ITAM (human CD79a Tyr210, mouse CD79a Tyr204) that can bind BLNK and Nck once phosphorylated,[21][22][23] and is critical for BCR mediated B cell proliferation and B1 cell development.[24] CD79a ITAM tyrosine phosphorylation and signaling is negatively regulated by serine and threonine residues in direct proximity of the ITAM (human CD79a Ser197, Ser203, Thr209; mouse CD79a Ser191, Ser197, Thr203),[25][26] and play a role in limiting formation of bone marrow plasma cells secreting IgG2a and IgG2b.[19]

Diagnostic relevance

The CD79a protein is present on the surface of B-cells throughout their life cycle, and is absent on all other healthy cells, making it a highly reliable marker for B-cells in immunohistochemistry. The protein remains present when B-cells transform into active plasma cells, and is also present in virtually all B-cell neoplasms, including B-cell lymphomas, plasmacytomas, and myelomas. It is also present in abnormal lymphocytes associated with some cases of Hodgkins disease. Because even on B-cell precursors, it can be used to stain a wider range of cells than can the alternative B-cell marker CD20, but the latter is more commonly retained on mature B-cell lymphomas, so that the two are often used together in immunohistochemistry panels.[2]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 "Entrez Gene: CD79A CD79a molecule, immunoglobulin-associated alpha". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=973. 
  2. ↑ 2.0 2.1 Anthony S-Y, Leong; Cooper, Kumarason; Leong, F Joel W-M (2003). Manual of Diagnostic Cytology (2 ed.). Greenwich Medical Media, Ltd.. pp. XX. ISBN 1-84110-100-1. 
  3. ↑ 3.0 3.1 Online Mendelian Inheritance in Man (OMIM) 613501
  4. ↑ "B lymphocyte lineage-restricted expression of mb-1, a gene with CD3-like structural properties". The EMBO Journal 7 (11): 3457–64. Nov 1988. doi:10.1002/j.1460-2075.1988.tb03220.x. PMID 2463161. 
  5. ↑ "Molecular cloning and expression pattern of a human gene homologous to the murine mb-1 gene". Journal of Immunology 148 (5): 1526–31. Mar 1992. doi:10.4049/jimmunol.148.5.1526. PMID 1538135. 
  6. ↑ "Molecular cloning of the Ig-alpha subunit of the human B-cell antigen receptor complex". Immunogenetics 36 (4): 266–9. 1992. doi:10.1007/bf00215058. PMID 1639443. 
  7. ↑ "The mouse B cell-specific mb-1 gene encodes an immunoreceptor tyrosine-based activation motif (ITAM) protein that may be evolutionarily conserved in diverse species by purifying selection". Molecular Biology Reports 39 (3): 3185–96. Mar 2012. doi:10.1007/s11033-011-1085-7. PMID 21688146. 
  8. ↑ "Origin and evolution of the adaptive immune system: genetic events and selective pressures". Nature Reviews Genetics 11 (1): 47–59. Jan 2010. doi:10.1038/nrg2703. PMID 19997068. 
  9. ↑ "Antigen receptor tail clue". Nature 338 (6214): 383–4. Mar 1989. doi:10.1038/338383b0. PMID 2927501. Bibcode: 1989Natur.338..383R. 
  10. ↑ "Antigen and Fc receptor signaling. The awesome power of the immunoreceptor tyrosine-based activation motif (ITAM)". Journal of Immunology 155 (7): 3281–5. Oct 1995. doi:10.4049/jimmunol.155.7.3281. PMID 7561018. 
  11. ↑ "Antigen receptors on B lymphocytes". Annual Review of Immunology 10 (1): 97–121. 1992. doi:10.1146/annurev.iy.10.040192.000525. PMID 1591006. 
  12. ↑ Yang, Jianying; Reth, Michael (September 2010). "Oligomeric organization of the B-cell antigen receptor on resting cells" (in en). Nature 467 (7314): 465–469. doi:10.1038/nature09357. ISSN 1476-4687. PMID 20818374. Bibcode: 2010Natur.467..465Y. https://www.nature.com/articles/nature09357. 
  13. ↑ "B cell progenitors are arrested in maturation but have intact VDJ recombination in the absence of Ig-alpha and Ig-beta". Journal of Immunology 169 (2): 865–72. Jul 2002. doi:10.4049/jimmunol.169.2.865. PMID 12097390. 
  14. ↑ "Mutations in Igalpha (CD79a) result in a complete block in B-cell development". The Journal of Clinical Investigation 104 (8): 1115–21. Oct 1999. doi:10.1172/JCI7696. PMID 10525050. 
  15. ↑ "Novel Igalpha (CD79a) gene mutation in a Turkish patient with B cell-deficient agammaglobulinemia". American Journal of Medical Genetics 108 (4): 333–6. Apr 2002. doi:10.1002/ajmg.10296. PMID 11920841. 
  16. ↑ "Dual role of the tyrosine activation motif of the Ig-alpha protein during signal transduction via the B cell antigen receptor". The EMBO Journal 13 (1): 83–9. Jan 1994. doi:10.1002/j.1460-2075.1994.tb06237.x. PMID 8306975. 
  17. ↑ "Initiation and processing of signals from the B cell antigen receptor". Annual Review of Immunology 15 (1): 453–79. 1997. doi:10.1146/annurev.immunol.15.1.453. PMID 9143696. 
  18. ↑ 18.0 18.1 "Ig beta tyrosine residues contribute to the control of B cell receptor signaling by regulating receptor internalization". The Journal of Experimental Medicine 203 (7): 1785–94. Jul 2006. doi:10.1084/jem.20060221. PMID 16818674. 
  19. ↑ 19.0 19.1 "Cytoplasmic Ig alpha serine/threonines fine-tune Ig alpha tyrosine phosphorylation and limit bone marrow plasma cell formation". Journal of Immunology 187 (6): 2853–8. Sep 2011. doi:10.4049/jimmunol.1101143. PMID 21841126. 
  20. ↑ "Interference with immunoglobulin (Ig)alpha immunoreceptor tyrosine-based activation motif (ITAM) phosphorylation modulates or blocks B cell development, depending on the availability of an Igbeta cytoplasmic tail". The Journal of Experimental Medicine 194 (4): 455–69. Aug 2001. doi:10.1084/jem.194.4.455. PMID 11514602. 
  21. ↑ "Association of SLP-65/BLNK with the B cell antigen receptor through a non-ITAM tyrosine of Ig-alpha". European Journal of Immunology 31 (7): 2126–34. Jul 2001. doi:10.1002/1521-4141(200107)31:7<2126::aid-immu2126>3.0.co;2-o. PMID 11449366. 
  22. ↑ "The direct recruitment of BLNK to immunoglobulin alpha couples the B-cell antigen receptor to distal signaling pathways". Molecular and Cellular Biology 22 (8): 2524–35. Apr 2002. doi:10.1128/MCB.22.8.2524-2535.2002. PMID 11909947. 
  23. ↑ "Nck-mediated recruitment of BCAP to the BCR regulates the PI(3)K-Akt pathway in B cells". Nature Immunology 14 (9): 966–75. Sep 2013. doi:10.1038/ni.2685. PMID 23913047. 
  24. ↑ "The B cell receptor promotes B cell activation and proliferation through a non-ITAM tyrosine in the Igalpha cytoplasmic domain". Immunity 25 (1): 55–65. Jul 2006. doi:10.1016/j.immuni.2006.04.014. PMID 16860757. 
  25. ↑ "The serine and threonine residues in the Ig-alpha cytoplasmic tail negatively regulate immunoreceptor tyrosine-based activation motif-mediated signal transduction". Proceedings of the National Academy of Sciences of the United States of America 97 (15): 8451–4. Jul 2000. doi:10.1073/pnas.97.15.8451. PMID 10900006. Bibcode: 2000PNAS...97.8451M. 
  26. ↑ "Syk is a dual-specificity kinase that self-regulates the signal output from the B-cell antigen receptor". Proceedings of the National Academy of Sciences of the United States of America 107 (43): 18563–8. Oct 2010. doi:10.1073/pnas.1009048107. PMID 20940318. Bibcode: 2010PNAS..10718563H. 

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



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