This web page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison.
CTLA4 Protein OverveiwCytotoxic T-lymphocyte protein 4 is a single pass type I membrane protein expressed on the surface of T cells. The proteins serves as a key regulator to the immune response by transmitting inhibitory signals during T cell activation. Subtle changes in the membrane expression or function of the molecule can lead to autoimmune disorders, such as Grave's Disease. The lose of negative regulation results in an overactive and aberrant immune response. [1]
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Structure / LocalizationStructure
The 223 amino acid protein consists of a signal sequence, a ligand-binding domain, a transmembrane domain, and a cytoplasmic tail. See [Motifs and Domains] for a detailed review of the protein structure. There are several splice variants that produce different isoforms of the protein. The membrane bound receptor isoform functions as a homodimer (figure 2). [2] Cellular Localization
CTLA4 is primarily an intracellular protein found in transport vesicles whose surface expression is highly regulated. Only during immune stimulation does surface expression slightly increase, followed by rapid internalization. Tight regulation of CTLA4 surface expression is critical for maintaing a controlled but effective immune response. [2] Tissue Localization CTLA4 is expressed in lymphoid tissue, with surface expression increasing during T cell activation. The highest level of CTLA surface expression is still about 30 fold less than CD28, the main simulatory coreceptor of the immune response. [3] |
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CTLA4 Protein FunctionDuring stimulation of T cells, an antigen presenting cell comes into close proximity with a T cell forming an immunological synapse. The binding of the T cell receptor and the costimulatory molecule, CD28, to their respective ligands results in T cell activation. T cell activation also induces the increased surface expression of CTLA4 through a number of mechanisms that increase the trafficking and stabilization of CTLA4 at the membrane. [4]
Once localized to the membrane CTLA4 can act as a negative regulator of the immune response:
The role of CTLA4 as a negative modulator of T cells is critical for the overall effectiveness of an immune response. |
References
[1] Teft, W. A., Kirchhof, M. G., and Madrenas, J. (2006) A molecular perspective of CTLA-4 function. Annu. Rev. Immunol. 24, 65–97. doi: 10.1146/annurev.immunol.24.021605.090535
[2] Valk E. Rudd C. Schneider H. 2008. CTLA-4 trafficking and surface expression. Trends in Immunology, 29, 272-279. doi:10.1016/j.it.2008.02.011
[3] http://www.uniprot.org/uniprot/P16410
[4] April K.S. Salama and F. Stephen Hodi. 2011. Cytotoxic T-Lymphocyte Antigen-4. Clin Cancer Res; 17:4622-4628. doi: 10.1158/1078-0432.CCR-10-2232
[5] Anjos S, Nguyen A, Ounissi-Benkalha H,Tessier MC, Polychronakos C. 2002. A common autoimmunity predisposing signal peptide variant of the cytotoxicT-lymphocyte antigen 4 results in inefficient glycosylation of the susceptibility allele. J. Biol. Chem. 277:46478–86. doi: 10.1074/jbc.M206894200
[1] Teft, W. A., Kirchhof, M. G., and Madrenas, J. (2006) A molecular perspective of CTLA-4 function. Annu. Rev. Immunol. 24, 65–97. doi: 10.1146/annurev.immunol.24.021605.090535
[2] Valk E. Rudd C. Schneider H. 2008. CTLA-4 trafficking and surface expression. Trends in Immunology, 29, 272-279. doi:10.1016/j.it.2008.02.011
[3] http://www.uniprot.org/uniprot/P16410
[4] April K.S. Salama and F. Stephen Hodi. 2011. Cytotoxic T-Lymphocyte Antigen-4. Clin Cancer Res; 17:4622-4628. doi: 10.1158/1078-0432.CCR-10-2232
[5] Anjos S, Nguyen A, Ounissi-Benkalha H,Tessier MC, Polychronakos C. 2002. A common autoimmunity predisposing signal peptide variant of the cytotoxicT-lymphocyte antigen 4 results in inefficient glycosylation of the susceptibility allele. J. Biol. Chem. 277:46478–86. doi: 10.1074/jbc.M206894200