View source for 6mjo


==CRYSTAL STRUCTURE OF RHESUS MACAQUE (MACACA MULATTA) FC-GAMMA RECEPTOR III==
<StructureSection load='6mjo' size='340' side='right'caption='[[6mjo]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6mjo]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Macaca_mulatta Macaca mulatta]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MJO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6MJO FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6mjo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mjo OCA], [https://pdbe.org/6mjo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mjo RCSB], [https://www.ebi.ac.uk/pdbsum/6mjo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mjo ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/FCG3A_MACMU 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]<ref>PMID:33208458</ref> <ref>PMID:34485821</ref> 
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== Publication Abstract from PubMed ==
Fc mediated effector functions of antibodies play important roles in immunotherapies and vaccine efficacy but assessing those functions in animal models can be challenging due to species differences. Rhesus macaques, Macaca mulatta (Mm) share approximately 93% sequence identity with humans but display important differences in their adaptive immune system that complicates their use in validating therapeutics and vaccines that rely on Fc effector functions. In contrast to humans, macaques only have one low affinity FcgammaRIII receptor, CD16, which shares a polymorphism at position 158 with human FcgammaRIIIa with Ile(158) and Val(158) variants. Here we describe structure-function relationships of the Ile/Val(158) polymorphism in Mm FcgammaRIII. Our data indicate that the affinity of the allelic variants of Mm FcgammaRIII for the macaque IgG subclasses vary greatly with changes in glycan composition both on the Fc and the receptor. However, unlike the human Phe/Val(158) polymorphism in FcgammaRIIIa, the higher affinity variant corresponds to the larger, more hydrophobic side chain, Ile, even though it is not directly involved in the binding interface. Instead, this side chain appears to modulate glycan-glycan interactions at the Fc/FcgammaRIII interface. Furthermore, changes in glycan composition on the receptor have a greater effect for the Val(158) variant such that with oligomannose type glycans and with glycans only on Asn(45) and Asn(162), Val(158) becomes the variant with higher affinity to Fc. These results have implications not only for the better interpretation of nonhuman primate studies but also for studies performed with human effector cells carrying different FcgammaRIIIa alleles.

Decoding human-macaque interspecies differences in Fc-effector functions: The structural basis for CD16-dependent effector function in Rhesus macaques.,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 Front Immunol. 2022 Sep 5;13:960411. doi: 10.3389/fimmu.2022.960411. eCollection , 2022. PMID:36131913<ref>PMID:36131913</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6mjo" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Macaca mulatta]]
[[Category: Pazgier M]]
[[Category: Tolbert WD]]
[[Category: Van V]]