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CD79A

From Wikipedia, the free encyclopedia

CD79A
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCD79A, IGA, MB-1, CD79a molecule, MB1, IGAlpha
External IDsOMIM: 112205; MGI: 101774; HomoloGene: 31053; GeneCards: CD79A; OMA:CD79A - orthologs
Orthologs
SpeciesHumanMouse
Entrez

973

12518

Ensembl

ENSG00000105369

ENSMUSG00000003379

UniProt

P11912

P11911

RefSeq (mRNA)

NM_021601
NM_001783

NM_007655

RefSeq (protein)

NP_001774
NP_067612

NP_031681

Location (UCSC)Chr 19: 41.88 – 41.88 MbChr 7: 24.6 – 24.6 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5]

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.[6]

It is associated with agammaglobulinemia-3.[7]

Gene

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The mouse CD79A gene, then called mb-1, was cloned in the late 1980s,[8] followed by the discovery of human CD79A in the early 1990s.[9][10] It is a short gene, 4.3 kb in length, with 5 exons encoding for 2 splice variants resulting in 2 isoforms.[5]

CD79A is conserved and abundant among ray-finned fish (actinopterygii) but not in the evolutionarily more ancient chondrichthyes such as shark.[11] 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.[12]

Structure

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CD79a is a membrane protein with an extracellular immunoglobulin domain, a single span transmembrane region and a short cytoplasmic domain.[5] The cytoplasmic domain contains multiple phosphorylation sites including a conserved dual phosphotyrosine binding motif, termed immunotyrosine-based activation motif (ITAM).[13][14] 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.[5] CD79a has several cysteine residues, one of which forms covalent bonds with CD79b.[15]

Function

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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.[16] 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.[17] 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.[7][18][19]

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.[20][21] 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.[22][23] 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.[22][24] 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,[25][26][27] and is critical for BCR mediated B cell proliferation and B1 cell development.[28] 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),[29][30] and play a role in limiting formation of bone marrow plasma cells secreting IgG2a and IgG2b.[23]

Diagnostic relevance

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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.[6]

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000105369 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000003379 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b c d "Entrez Gene: CD79A CD79a molecule, immunoglobulin-associated alpha".
  6. ^ a b Leong AS, Cooper K, Leong FJ (2003). Manual of Diagnostic Cytology (2nd ed.). Greenwich Medical Media, Ltd. pp. XX. ISBN 1-84110-100-1.
  7. ^ a b Online Mendelian Inheritance in Man (OMIM): 613501
  8. ^ Sakaguchi N, Kashiwamura S, Kimoto M, Thalmann P, Melchers F (November 1988). "B lymphocyte lineage-restricted expression of mb-1, a gene with CD3-like structural properties". The EMBO Journal. 7 (11): 3457–3464. doi:10.1002/j.1460-2075.1988.tb03220.x. PMC 454845. PMID 2463161.
  9. ^ Ha HJ, Kubagawa H, Burrows PD (March 1992). "Molecular cloning and expression pattern of a human gene homologous to the murine mb-1 gene". Journal of Immunology. 148 (5): 1526–1531. doi:10.4049/jimmunol.148.5.1526. PMID 1538135. S2CID 22129592.
  10. ^ Flaswinkel H, Reth M (1992). "Molecular cloning of the Ig-alpha subunit of the human B-cell antigen receptor complex". Immunogenetics. 36 (4): 266–269. doi:10.1007/bf00215058. PMID 1639443. S2CID 28622219.
  11. ^ Sims R, Vandergon VO, Malone CS (March 2012). "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): 3185–3196. doi:10.1007/s11033-011-1085-7. PMC 4667979. PMID 21688146.
  12. ^ Flajnik MF, Kasahara M (January 2010). "Origin and evolution of the adaptive immune system: genetic events and selective pressures". Nature Reviews. Genetics. 11 (1): 47–59. doi:10.1038/nrg2703. PMC 3805090. PMID 19997068.
  13. ^ Reth M (March 1989). "Antigen receptor tail clue". Nature. 338 (6214): 383–384. Bibcode:1989Natur.338..383R. doi:10.1038/338383b0. PMID 2927501. S2CID 5213145.
  14. ^ Cambier JC (October 1995). "Antigen and Fc receptor signaling. The awesome power of the immunoreceptor tyrosine-based activation motif (ITAM)". Journal of Immunology. 155 (7): 3281–3285. doi:10.4049/jimmunol.155.7.3281. PMID 7561018. S2CID 996547.
  15. ^ Reth M (1992). "Antigen receptors on B lymphocytes". Annual Review of Immunology. 10 (1): 97–121. doi:10.1146/annurev.iy.10.040192.000525. PMID 1591006.
  16. ^ Yang J, Reth M (September 2010). "Oligomeric organization of the B-cell antigen receptor on resting cells". Nature. 467 (7314): 465–469. Bibcode:2010Natur.467..465Y. doi:10.1038/nature09357. PMID 20818374. S2CID 3261220.
  17. ^ Pelanda R, Braun U, Hobeika E, Nussenzweig MC, Reth M (July 2002). "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): 865–872. doi:10.4049/jimmunol.169.2.865. PMID 12097390.
  18. ^ Minegishi Y, Coustan-Smith E, Rapalus L, Ersoy F, Campana D, Conley ME (October 1999). "Mutations in Igalpha (CD79a) result in a complete block in B-cell development". The Journal of Clinical Investigation. 104 (8): 1115–1121. doi:10.1172/JCI7696. PMC 408581. PMID 10525050.
  19. ^ Wang Y, Kanegane H, Sanal O, Tezcan I, Ersoy F, Futatani T, et al. (April 2002). "Novel Igalpha (CD79a) gene mutation in a Turkish patient with B cell-deficient agammaglobulinemia". American Journal of Medical Genetics. 108 (4): 333–336. doi:10.1002/ajmg.10296. PMID 11920841.
  20. ^ Flaswinkel H, Reth M (January 1994). "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): 83–89. doi:10.1002/j.1460-2075.1994.tb06237.x. PMC 394781. PMID 8306975.
  21. ^ Reth M, Wienands J (1997). "Initiation and processing of signals from the B cell antigen receptor". Annual Review of Immunology. 15 (1): 453–479. doi:10.1146/annurev.immunol.15.1.453. PMID 9143696.
  22. ^ a b Gazumyan A, Reichlin A, Nussenzweig MC (July 2006). "Ig beta tyrosine residues contribute to the control of B cell receptor signaling by regulating receptor internalization". The Journal of Experimental Medicine. 203 (7): 1785–1794. doi:10.1084/jem.20060221. PMC 2118343. PMID 16818674.
  23. ^ a b Patterson HC, Kraus M, Wang D, Shahsafaei A, Henderson JM, Seagal J, et al. (September 2011). "Cytoplasmic Ig alpha serine/threonines fine-tune Ig alpha tyrosine phosphorylation and limit bone marrow plasma cell formation". Journal of Immunology. 187 (6): 2853–2858. doi:10.4049/jimmunol.1101143. PMC 3169759. PMID 21841126.
  24. ^ Kraus M, Pao LI, Reichlin A, Hu Y, Canono B, Cambier JC, et al. (August 2001). "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): 455–469. doi:10.1084/jem.194.4.455. PMC 2193498. PMID 11514602.
  25. ^ Engels N, Wollscheid B, Wienands J (July 2001). "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): 2126–2134. doi:10.1002/1521-4141(200107)31:7<2126::aid-immu2126>3.0.co;2-o. PMID 11449366. S2CID 31494726.
  26. ^ Kabak S, Skaggs BJ, Gold MR, Affolter M, West KL, Foster MS, et al. (April 2002). "The direct recruitment of BLNK to immunoglobulin alpha couples the B-cell antigen receptor to distal signaling pathways". Molecular and Cellular Biology. 22 (8): 2524–2535. doi:10.1128/MCB.22.8.2524-2535.2002. PMC 133735. PMID 11909947.
  27. ^ Castello A, Gaya M, Tucholski J, Oellerich T, Lu KH, Tafuri A, et al. (September 2013). "Nck-mediated recruitment of BCAP to the BCR regulates the PI(3)K-Akt pathway in B cells". Nature Immunology. 14 (9): 966–975. doi:10.1038/ni.2685. PMID 23913047. S2CID 2532325.
  28. ^ Patterson HC, Kraus M, Kim YM, Ploegh H, Rajewsky K (July 2006). "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. doi:10.1016/j.immuni.2006.04.014. PMID 16860757.
  29. ^ Müller R, Wienands J, Reth M (July 2000). "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): 8451–8454. Bibcode:2000PNAS...97.8451M. doi:10.1073/pnas.97.15.8451. PMC 26968. PMID 10900006.
  30. ^ Heizmann B, Reth M, Infantino S (October 2010). "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): 18563–18568. Bibcode:2010PNAS..10718563H. doi:10.1073/pnas.1009048107. PMC 2972992. PMID 20940318.

Further reading

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

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