CD4: Wikis

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CD4 molecule

Crystallographic structure of the V-set and C2 domains of human CD4.[1]
Available structures
1cdh, 1cdi, 1cdj, 1cdu, 1cdy, 1g9m, 1g9n, 1gc1, 1jl4, 1q68, 1rzj, 1rzk, 1wio, 1wip, 1wiq, 2b4c, 2nxy, 2nxz, 2ny0, 2ny1, 2ny2, 2ny3, 2ny4, 2ny5, 2ny6, 3cd4
Identifiers
Symbols CD4; CD4mut
External IDs OMIM186940 MGI88335 HomoloGene513 GeneCards: CD4 Gene
RNA expression pattern
PBB GE CD4 203547 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 920 12504
Ensembl ENSG00000010610 ENSMUSG00000023274
UniProt P01730 O55054
RefSeq (mRNA) NM_000616 NM_013488
RefSeq (protein) NP_000607 NP_038516
Location (UCSC) Chr 12:
6.77 - 6.8 Mb
Chr 6:
124.83 - 124.85 Mb
PubMed search [1] [2]

CD4 (cluster of differentiation 4) is a glycoprotein expressed on the surface of T helper cells, regulatory T cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 (after the OKT4 monoclonal antibody that reacted with it) before being named CD4 in 1984.[2] In humans, the CD4 protein is encoded by the CD4 gene.[3][4]

Contents

Function

CD4 is a co-receptor that assists the T cell receptor (TCR) to activate its T cell following an interaction with an antigen presenting cell. Using its portion that resides inside the T cell, CD4 amplifies the signal generated by the TCR by recruiting an enzyme, known as the tyrosine kinase lck, which is essential for activating many molecules involved in the signaling cascade of an activated T cell. CD4 also interacts directly with MHC class II molecules on the surface of the antigen presenting cell using its extracellular domain.

Structure

Schematic representation of CD4 receptor.

Like many cell surface receptors/markers, CD4 is a member of the immunoglobulin superfamily.

It has four immunoglobulin domains (D1 to D4) that are exposed on the extracellular surface of the cell:

  • D1 and D3 resemble immunoglobulin variable (IgV) domains.
  • D2 and D4 resemble immunoglobulin constant (IgC) domains.

CD4 uses its D1 domain to interact with the β2-domain of MHC class II molecules. T cells expressing CD4 molecules (and not CD8) on their surface, therefore, are specific for antigens presented by MHC II and not by MHC class I (they are MHC class II-restricted).

The short cytoplasmic/intracellular tail (C) of CD4 contains a special sequence of amino acids that allow it to interact with the lck molecule described above.

Role in HIV infection

TCR-MHC bindings

CD4 is a primary receptor used by HIV-1 to gain entry into host T cells.

HIV-1 attaches to CD4 with a protein in its viral envelope known as gp120. The binding to CD4 creates a shift in the conformation of gp120 allowing HIV-1 to bind to two other surface receptors on the host cell, the chemokine receptors CCR5 or CXCR4, depending on whether HIV is infecting a macrophage or T-helper cell. Following a structural change in another viral protein (gp41), HIV inserts a fusion peptide into the host cell that allows the outer membrane of the virus to fuse with the cell membrane.

HIV infection leads to a progressive reduction in the number of T cells possessing CD4 receptors. Therefore, medical professionals refer to the CD4 count to decide when to begin treatment for HIV-infected patients. Normal blood values are more than 1x109/L.[5]

Role in HIV treatments

CD4 tests measure the number of T cells containing the CD4 receptor. Results are usually expressed in the number of cells per microliter (or mm3) of blood. While CD4 tests are not an HIV test in that they do not check the presence of viral DNA, or specific antibodies, they are used to assess the immune system of patients. Patients often undergo treatments when the CD4 count reaches a low point, around 200 cells per microliter. Medical professionals also refer to CD4 tests to determine the efficacy of the treatment.

Blood content

Reference ranges for blood tests of white blood cells, comparing CD4+ cell amount (shown in green-yellow) with other cells.

Interactions

CD4 has been shown to interact with SPG21,[6] Lck[7][8] and Protein unc-119 homolog.[9]

References

  1. ^ PDB 1cdh; Ryu SE, Truneh A, Sweet RW, Hendrickson WA (January 1994). "Structures of an HIV and MHC binding fragment from human CD4 as refined in two crystal lattices". Structure 2 (1): 59–74. PMID 8075984.  
  2. ^ Alain Bernard (1984). Leucocyte typing: human leucocyte differentiation antigens detected by monoclonal antibodies: specification, classification, nomenclature: [report on the first international references workshop sponsored by INSERM, WHO and IUIS]. Berlin: Springer. pp. pages 45–48. ISBN 0-387-12056-4.  
  3. ^ Isobe M, Huebner K, Maddon PJ, Littman DR, Axel R, Croce CM (June 1986). "The gene encoding the T-cell surface protein T4 is located on human chromosome 12". Proc. Natl. Acad. Sci. U.S.A. 83 (12): 4399–402. doi:10.1073/pnas.83.12.4399. PMID 3086883. PMC 323740. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=3086883.  
  4. ^ Ansari-Lari MA, Muzny DM, Lu J, Lu F, Lilley CE, Spanos S, Malley T, Gibbs RA (April 1996). "A gene-rich cluster between the CD4 and triosephosphate isomerase genes at human chromosome 12p13". Genome Res. 6 (4): 314–26. doi:10.1101/gr.6.4.314. PMID 8723724. http://www.genome.org/cgi/pmidlookup?view=long&pmid=8723724.  
  5. ^ Fisher, Bruce; Harvey, Richard P.; Champe, Pamela C. (2007). Lippincott's Illustrated Reviews: Microbiology (Lippincott's Illustrated Reviews Series). Hagerstown, MD: Lippincott Williams & Wilkins. ISBN 0-7817-8215-5.   Page 300
  6. ^ Zeitlmann, L; Sirim P, Kremmer E, Kolanus W (Mar. 2001). "Cloning of ACP33 as a novel intracellular ligand of CD4". J. Biol. Chem. (United States) 276 (12): 9123–32. doi:10.1074/jbc.M009270200. ISSN 0021-9258. PMID 11113139.  
  7. ^ Hawash, Ibrahim Y; Hu X Eric, Adal Adiam, Cassady John M, Geahlen Robert L, Harrison Marietta L (Apr. 2002). "The oxygen-substituted palmitic acid analogue, 13-oxypalmitic acid, inhibits Lck localization to lipid rafts and T cell signaling". Biochim. Biophys. Acta (Netherlands) 1589 (2): 140–50. ISSN 0006-3002. PMID 12007789.  
  8. ^ Foti, Michelangelo; Phelouzat Marie-Anne, Holm Asa, Rasmusson Birgitta J, Carpentier Jean-Louis (Feb. 2002). "p56Lck anchors CD4 to distinct microdomains on microvilli". Proc. Natl. Acad. Sci. U.S.A. (United States) 99 (4): 2008–13. doi:10.1073/pnas.042689099. ISSN 0027-8424. PMID 11854499.  
  9. ^ Gorska, Magdalena M; Stafford Susan J, Cen Osman, Sur Sanjiv, Alam Rafeul (Feb. 2004). "Unc119, a novel activator of Lck/Fyn, is essential for T cell activation". J. Exp. Med. (United States) 199 (3): 369–79. doi:10.1084/jem. 20030589. ISSN 0022-1007. PMID 14757743.  

Further reading

  • Miceli MC, Parnes JR (1993). "Role of CD4 and CD8 in T cell activation and differentiation". Adv. Immunol. 53: 59–122. doi:10.1016/S0065-2776(08)60498-8. PMID 8512039.  
  • Geyer M, Fackler OT, Peterlin BM (2001). "Structure--function relationships in HIV-1 Nef". EMBO Rep. 2 (7): 580–5. doi:10.1093/embo-reports/kve141. PMID 11463741.  
  • Greenway AL, Holloway G, McPhee DA, et al. (2004). "HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication". J. Biosci. 28 (3): 323–35. doi:10.1007/BF02970151. PMID 12734410.  
  • Bénichou S, Benmerah A (2003). "[The HIV nef and the Kaposi-sarcoma-associated virus K3/K5 proteins: "parasites"of the endocytosis pathway]". Med Sci (Paris) 19 (1): 100–6. PMID 12836198.  
  • Leavitt SA, SchOn A, Klein JC, et al. (2004). "Interactions of HIV-1 proteins gp120 and Nef with cellular partners define a novel allosteric paradigm". Curr. Protein Pept. Sci. 5 (1): 1–8. doi:10.2174/1389203043486955. PMID 14965316.  
  • Tolstrup M, Ostergaard L, Laursen AL, et al. (2004). "HIV/SIV escape from immune surveillance: focus on Nef". Curr. HIV Res. 2 (2): 141–51. doi:10.2174/1570162043484924. PMID 15078178.  
  • Hout DR, Mulcahy ER, Pacyniak E, et al. (2005). "Vpu: a multifunctional protein that enhances the pathogenesis of human immunodeficiency virus type 1". Curr. HIV Res. 2 (3): 255–70. doi:10.2174/1570162043351246. PMID 15279589.  
  • Joseph AM, Kumar M, Mitra D (2005). "Nef: "necessary and enforcing factor" in HIV infection". Curr. HIV Res. 3 (1): 87–94. doi:10.2174/1570162052773013. PMID 15638726.  
  • Anderson JL, Hope TJ (2005). "HIV accessory proteins and surviving the host cell". Current HIV/AIDS reports 1 (1): 47–53. doi:10.1007/s11904-004-0007-x. PMID 16091223.  
  • Li L, Li HS, Pauza CD, et al. (2006). "Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions". Cell Res. 15 (11-12): 923–34. doi:10.1038/sj.cr.7290370. PMID 16354571.  
  • Stove V, Verhasselt B (2006). "Modelling thymic HIV-1 Nef effects". Curr. HIV Res. 4 (1): 57–64. doi:10.2174/157016206775197583. PMID 16454711.  

External links

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Wiktionary

Up to date as of January 14, 2010

Definition from Wiktionary, a free dictionary

English

Etymology

Abbreviation

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Wikipedia

CD4

  1. (immunology) A glycoprotein found on the surface of helper T cells; in humans, it enables the HIV virus to enter a cell

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