CTLA-4

Function

CTLA4 or Cytotoxic T-Lymphocyte Associated protein 4 or CD152 is a member of the immunoglobulin superfamily that is expressed by activated T cells and transmits an inhibitory signal to T cells. CTLA4 is homologous to the T-cell co-stimulatory protein, CD28, and both molecules bind to CD80 and CD86, also called B7-1 and B7-2 respectively, on antigen-presenting cells^[1]. CTLA-4 binds CD80 and CD86 with greater affinity and avidity than CD28 thus enabling it to outcompete CD28 for its ligands. CTLA4 transmits an inhibitory signal to T cells,[10][11][12][7] whereas CD28 transmits a stimulatory signal.[13][14] CTLA4 is also found in regulatory T cells (Tregs) and contributes to their inhibitory function. T cell activation through the T cell receptor and CD28 leads to increased expression of CTLA-4.

Disease

Variants in this gene have been associated with Type 1 diabetes^[2], Graves' disease, Hashimoto's thyroiditis, celiac disease, systemic lupus erythematosus, thyroid-associated orbitopathy, primary biliary cirrhosis and other autoimmune diseases.

Structural highlights

The protein contains an extracellular V domain, a transmembrane domain, and a cytoplasmic tail. Alternate splice variants, encoding different isoforms, have been characterized. The membrane-bound isoform functions as a homodimer interconnected by a disulfide bond, while the soluble isoform functions as a monomer. The intracellular domain is similar to that of CD28. The complex between CTLA-4 and CD80 is formed mostly by hydrophobic contacts^[3].

3D structures of CTLA-4

Updated on 10-February-2021

2x44, 3osk - hCTLA-4 - human

1ah1 - hCTLA-4 - NMR
5ggv, 5tru, 5xj3, 6rp8, 6xy2 - hCTLA-4 + antibody
6rpj, 6rqm - hCTLA-4 + nanobody
1i8l - hCTLA-4 + CD80
1i85 - hCTLA-4 + CD86
3bx7 - hCTLA-4 + LCN2
7cio - hCTLA-4 + PI3K
4kkn - CTLA-4 - bovine
1dqt, 5e56 - mCTLA-4 - mouse
5e5m - mCTLA-4 + nanobody

References

1. ↑ Van Coillie S, Wiernicki B, Xu J. Molecular and Cellular Functions of CTLA-4. Adv Exp Med Biol. 2020;1248:7-32. doi: 10.1007/978-981-15-3266-5_2. PMID:32185705 doi:http://dx.doi.org/10.1007/978-981-15-3266-5_2
2. ↑ Lee YJ, Huang FY, Lo FS, Wang WC, Hsu CH, Kao HA, Yang TY, Chang JG. Association of CTLA4 gene A-G polymorphism with type 1 diabetes in Chinese children. Clin Endocrinol (Oxf). 2000 Feb;52(2):153-7. doi:, 10.1046/j.1365-2265.2000.00929.x. PMID:10671941 doi:http://dx.doi.org/10.1046/j.1365-2265.2000.00929.x
3. ↑ Stamper CC, Zhang Y, Tobin JF, Erbe DV, Ikemizu S, Davis SJ, Stahl ML, Seehra J, Somers WS, Mosyak L. Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses. Nature. 2001 Mar 29;410(6828):608-11. PMID:11279502 doi:10.1038/35069118

References https://www.wikiwand.com/en/CTLA-4