| Structural highlights
Disease
FCG3A_HUMAN The disease is caused by mutations affecting the gene represented in this entry.[1] [2] [3] [4]
Function
FCG3A_HUMAN Receptor for the Fc region of IgG. Binds complexed or aggregated IgG and also monomeric IgG. Mediates antibody-dependent cellular cytotoxicity (ADCC) and other antibody-dependent responses, such as phagocytosis.[5] [6]
Publication Abstract from PubMed
Protein-protein interactions are essential for the control of cellular functions and are critical for regulation of the immune system. One example is the binding of Fc regions of IgG to the Fc gamma receptors (FcgammaRs). High sequence identity (98%) between the genes encoding FcgammaRIIIa (expressed on macrophages and natural killer cells) and FcgammaRIIIb (expressed on neutrophils) has prevented the development of monospecific agents against these therapeutic targets. We now report the identification of FcgammaRIIIa-specific artificial binding proteins called "Affimer" that block IgG binding and abrogate FcgammaRIIIa-mediated downstream effector functions in macrophages, namely TNF release and phagocytosis. Cocrystal structures and molecular dynamics simulations have revealed the structural basis of this specificity for two Affimer proteins: One binds directly to the Fc binding site, whereas the other acts allosterically.
Affimer proteins inhibit immune complex binding to FcgammaRIIIa with high specificity through competitive and allosteric modes of action.,Robinson JI, Baxter EW, Owen RL, Thomsen M, Tomlinson DC, Waterhouse MP, Win SJ, Nettleship JE, Tiede C, Foster RJ, Owens RJ, Fishwick CWG, Harris SA, Goldman A, McPherson MJ, Morgan AW Proc Natl Acad Sci U S A. 2017 Dec 15. pii: 1707856115. doi:, 10.1073/pnas.1707856115. PMID:29247053[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Grier JT, Forbes LR, Monaco-Shawver L, Oshinsky J, Atkinson TP, Moody C, Pandey R, Campbell KS, Orange JS. Human immunodeficiency-causing mutation defines CD16 in spontaneous NK cell cytotoxicity. J Clin Invest. 2012 Oct 1;122(10):3769-80. doi: 10.1172/JCI64837. Epub 2012 Sep, 24. PMID:23006327 doi:http://dx.doi.org/10.1172/JCI64837
- ↑ Jawahar S, Moody C, Chan M, Finberg R, Geha R, Chatila T. Natural Killer (NK) cell deficiency associated with an epitope-deficient Fc receptor type IIIA (CD16-II). Clin Exp Immunol. 1996 Mar;103(3):408-13. PMID:8608639
- ↑ de Haas M, Koene HR, Kleijer M, de Vries E, Simsek S, van Tol MJ, Roos D, von dem Borne AE. A triallelic Fc gamma receptor type IIIA polymorphism influences the binding of human IgG by NK cell Fc gamma RIIIa. J Immunol. 1996 Apr 15;156(8):2948-55. PMID:8609432
- ↑ de Vries E, Koene HR, Vossen JM, Gratama JW, von dem Borne AE, Waaijer JL, Haraldsson A, de Haas M, van Tol MJ. Identification of an unusual Fc gamma receptor IIIa (CD16) on natural killer cells in a patient with recurrent infections. Blood. 1996 Oct 15;88(8):3022-7. PMID:8874200
- ↑ Ferrara C, Grau S, Jager C, Sondermann P, Brunker P, Waldhauer I, Hennig M, Ruf A, Rufer AC, Stihle M, Umana P, Benz J. Unique carbohydrate-carbohydrate interactions are required for high affinity binding between Fc{gamma}RIII and antibodies lacking core fucose. Proc Natl Acad Sci U S A. 2011 Jul 18. PMID:21768335 doi:10.1073/pnas.1108455108
- ↑ Mizushima T, Yagi H, Takemoto E, Shibata-Koyama M, Isoda Y, Iida S, Masuda K, Satoh M, Kato K. Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans. Genes Cells. 2011 Nov;16(11):1071-1080. doi:, 10.1111/j.1365-2443.2011.01552.x. PMID:22023369 doi:10.1111/j.1365-2443.2011.01552.x
- ↑ Robinson JI, Baxter EW, Owen RL, Thomsen M, Tomlinson DC, Waterhouse MP, Win SJ, Nettleship JE, Tiede C, Foster RJ, Owens RJ, Fishwick CWG, Harris SA, Goldman A, McPherson MJ, Morgan AW. Affimer proteins inhibit immune complex binding to FcgammaRIIIa with high specificity through competitive and allosteric modes of action. Proc Natl Acad Sci U S A. 2017 Dec 15. pii: 1707856115. doi:, 10.1073/pnas.1707856115. PMID:29247053 doi:http://dx.doi.org/10.1073/pnas.1707856115
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