6mjo

Structural highlights

Function

FCG3A_MACMU Receptor for the invariable Fc fragment of immunoglobulin gamma (IgG). Optimally activated upon binding of clustered antigen-IgG complexes displayed on cell surfaces, triggers lysis of antibody-coated cells, a process known as antibody-dependent cellular cytotoxicity (ADCC). Does not bind free monomeric IgG, thus avoiding inappropriate effector cell activation in the absence of antigenic trigger (PubMed:33208458). Mediates IgG effector functions on natural killer (NK) cells. Binds antigen-IgG complexes generated upon infection and triggers NK cell-dependent cytokine production and degranulation to limit viral load and propagation. Involved in the generation of memory-like adaptive NK cells capable to produce high amounts of IFNG and to efficiently eliminate virus-infected cells via ADCC. Regulates NK cell survival and proliferation, in particular by preventing NK cell progenitor apoptosis (By similarity). Fc-binding subunit that associates with CD247 and/or FCER1G adapters to form functional signaling complexes. Following the engagement of antigen-IgG complexes, triggers phosphorylation of immunoreceptor tyrosine-based activation motif (ITAM)-containing adapters with subsequent activation of phosphatidylinositol 3-kinase signaling and sustained elevation of intracellular calcium that ultimately drive NK cell activation. The ITAM-dependent signaling coupled to receptor phosphorylation by PKC mediates robust intracellular calcium flux that leads to production of pro-inflammatory cytokines, whereas in the absence of receptor phosphorylation it mainly activates phosphatidylinositol 3-kinase signaling leading to cell degranulation (By similarity). Costimulates NK cells and trigger lysis of target cells independently of IgG binding (By similarity). Mediates the antitumor activities of therapeutic antibodies. Upon ligation on monocytes triggers TNFA-dependent ADCC of IgG-coated tumor cells (By similarity). Mediates enhanced ADCC in response to afucosylated IgGs (PubMed:34485821).[UniProtKB:P08637]^{[1] [2]}

References

1. ↑ Grunst MW, Grandea AG 3rd, Janaka SK, Hammad I, Grimes P, Karl JA, Wiseman R, O'Connor DH, Evans DT. Functional Interactions of Common Allotypes of Rhesus Macaque FcgammaR2A and FcgammaR3A with Human and Macaque IgG Subclasses. J Immunol. 2020 Dec 15;205(12):3319-3332. doi: 10.4049/jimmunol.2000501. Epub, 2020 Nov 18. PMID:33208458 doi:http://dx.doi.org/10.4049/jimmunol.2000501
2. ↑ Mao C, Near R, Zhong X, Gao W. Cross-species higher sensitivities of FcgammaRIIIA/FcgammaRIV to afucosylated IgG for enhanced ADCC. Antib Ther. 2021 Aug 19;4(3):159-170. doi: 10.1093/abt/tbab016. eCollection 2021 , Jul. PMID:34485821 doi:http://dx.doi.org/10.1093/abt/tbab016
3. ↑ Tolbert WD, Gohain N, Kremer PG, Hederman AP, Nguyen DN, Van V, Sherburn R, Lewis GK, Finzi A, Pollara J, Ackerman ME, Barb AW, Pazgier M. Decoding human-macaque interspecies differences in Fc-effector functions: The structural basis for CD16-dependent effector function in Rhesus macaques. Front Immunol. 2022 Sep 5;13:960411. doi: 10.3389/fimmu.2022.960411. eCollection , 2022. PMID:36131913 doi:http://dx.doi.org/10.3389/fimmu.2022.960411