Crystal Structure of the Extracellular Domain of a Human FcγRIII

Zhang, Yihong; Boesen, Christian C.; Radaev, Sergei; Brööks, Andrëw G.; Fridman, Wolf‐Herman; Sautès-Fridman, Catheriné; Sun, Peter D.

doi:10.1016/s1074-7613(00)00038-8

Cited by 95 publications

(78 citation statements)

References 32 publications

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“…This broader recognition between pentraxins and FcγR is supported by their closely related structures, in that CRP and SAP share identical structural folds and form similar pentamers. Similarly, FcγR consist of homologous tandem Ig-like domains with IgG binding sites located in the two structurally similar membrane proximal domains (8,12,13). The permissive pentraxin-FcγR recognition led us to investigate further pentraxin recognition of other FcR, including an IgA receptor, FcαRI, and an IgE receptor, FcεRI.…”

Section: Resultsmentioning

confidence: 99%

Recognition and functional activation of the human IgA receptor (FcαRI) by C-reactive protein

Marjon

Marnell

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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C-reactive protein (CRP) is an important biomarker for inflammatory diseases. However, its role in inflammation beyond complement-mediated pathogen clearance remains poorly defined. We identified the major IgA receptor, FcαRI, as a ligand for pentraxins. CRP recognized FcαRI both in solution and on cells, and the pentraxin binding site on the receptor appears distinct from that recognized by IgA. Further competitive binding and mutational analysis showed that FcαRI bound to the effector face of CRP in a region overlapping with complement C1q and Fcγ receptor (FcγR) binding sites. CRP cross-linking of FcαRI resulted in extracellular signal-regulated kinase (ERK) phosphorylation, cytokine production, and degranulation in FcαRI-transfected RBL cells. In neutrophils, CRP induced FcαRI surface expression, phagocytosis, and TNF-α secretion. The ability of CRP to activate FcαRI defines a function for pentraxins in inflammatory responses involving neutrophils and macrophages. It also highlights the innate aspect of otherwise humoral immunity-associated antibody receptors.

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Section: Resultsmentioning

confidence: 99%

Recognition and functional activation of the human IgA receptor (FcαRI) by C-reactive protein

Marjon

Marnell

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Protein Expression, Purification, and Crystallization-The extracellular part of the human Fc␥RIIIb receptor, residues 1-172, was expressed as Escherichia coli inclusion bodies and then reconstituted in vitro as described previously (22). Fc fragments of human IgG1 antibody were prepared by the papain digestion as previously reported (23,24).…”

Section: Methodsmentioning

confidence: 99%

The Structure of a Human Type III Fcγ Receptor in Complex with Fc

Radaev

Motyka

Fridman

et al. 2001

Journal of Biological Chemistry

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Fc receptors, which are expressed on the majority of hematopoietic cells, play important roles in antibody-mediated immune responses. [3][4][5]. In addition to variations in affinity, each receptor displays distinct IgG subtype specificities. Unlike the high affinity receptors that can bind monomeric antibodies, the low affinity receptors preferentially bind to and are activated by immune complexes.Human Fc␥RIII exists as two isoforms, Fc␥RIIIA and Fc␥RIIIB, that share 96% sequence identity in their extracellular immunoglobulin-binding regions. Fc␥RIIIA is expressed on macrophages, mast cells, and natural killer cells as a transmembrane receptor. In contrast, Fc␥RIIIB, present exclusively on neutrophils, is anchored by a glycosyl-phosphatidylinositol linker to the plasma membrane. Although Fc␥RIIIA associates with the immunoreceptor tyrosine-based activation motif containing Fc⑀RI ␥-chain or the T cell receptor -chain for its signaling, Fc␥RIIIB lacks a signaling component. Nevertheless, it plays an active role in triggering Ca 2ϩ mobilization and in neutrophil degranulation (6, 7). In addition, Fc␥RIIIB, in conjunction with Fc␥RIIA, activates phagocytosis, degranulation, and the oxidative burst that leads to the clearance of opsonized pathogens by neutrophils. A soluble form of Fc␥RIIIB was reported to activate the CR3 complement receptordependent inflammatory process (8).The Fc binding region on Fc␥RII and Fc␥RIII has been identified through the work of chimeric receptors with Fc⑀RI as primarily the membrane proximal domain, including both the BC and FG loops. Further site-directed mutations have revealed several residues of the receptor critical to Fc binding (9 -11). Similar regions on the ␣-chain of Fc⑀RI were also identified to be critical for IgE binding affinity (12). The receptor binding site on Fc has been located through the construction of chimeric IgG molecules and mutational analysis at the lower hinge region, residues located in the hinge region between the C H 1 and C H 2 domains and immediately adjacent to the N terminus of the C H 2 domain of IgG (13-15). In particular, residues 234 -238 (Leu-Leu-Gly-Gly-Pro) of the lower hinge of IgG1 have been implicated in the receptor binding. The corresponding region of IgE has also been implicated in the Fc⑀RI binding (16). Apart from the lower hinge region, a few residues on the C H 2 domain of an IgG2b were also suggested to interact * This work was supported by the intramural research funding of NIAID, National Institutes of Health and by INSERM, Institut Curie, France. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. The recent crystal structures of Fc⑀RI␣, Fc␥RIIA, and Fc␥RIIB have each revealed a conserved Ig-like structure, with particularly the small hinge angle between the two Ig-like domains, which is unique to the Fc receptors (19 -21). We report here the crystal stru...

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“…[10][11][12][13][14] Interactions between circulating human PMNs and immune complexes are mediated via 2 low-affinity Fc␥ receptors, Fc␥RIIa (CD32a) and Fc␥RIIIb (CD16b), which are both thought to form homodimers and have distinct membrane-anchoring and -signaling capacities. [15][16][17][18][19] The cytoplasmic domain of Fc␥RIIa has a specialized immunoreceptor tyrosine-based activation motif, which on receptor cross-linking becomes tyrosine-phosphorylated by Srcfamily tyrosine kinases such as Fgr and Lyn. [20][21][22] Subsequent receptor association with Syk kinase and phosphoinositide 3-kinase results in phagocytosis, degranulation, respiratory burst, and antibody-dependent cellular cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Antiendothelial cell antibodies mediate enhanced leukocyte adhesion to cytokine-activated endothelial cells through a novel mechanism requiring cooperation between FcγRIIa and CXCR1/2

Florey

Johns

Esho

et al. 2007

Blood

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Antiendothelial cell antibodies (AECAs) are commonly detectable in diseases associated with vascular injury, including systemic lupus erythematosus (SLE), systemic sclerosis, Takayasu arteritis, Wegener granulomatosis, Behç et syndrome, and transplant arteriosclerosis. Here, we explore the hypothesis that these antibodies might augment polymorphonuclear leukocyte (PMN) adhesion to endothelium in inflammation. Initially, we established that a mouse IgG mAb bound to endothelial cells (ECs) significantly increased PMN adhesion to cytokine-stimulated endothelium in an Fc␥RIIa-dependent manner. Neutralizing antibodies, and adenoviral transduction of resting ECs, demonstrated that the combination of Eselectin, CXCR1/2, and ␤ 2 integrins is both necessary and sufficient for this process. We observed an identical mechanism using AECA IgG isolated directly from patients with SLE. Assembled immune complexes also enhanced PMN adhesion to endothelium, but, in contrast to adhesion because of AECAs, this process did not require CXCR1/2, was not inhibited by pertussis toxin, and was Fc␥RIIIb rather than Fc␥RIIa dependent. IntroductionThe recruitment of circulating polymorphonuclear leukocytes (PMNs) to sites of inflammation is mediated by a series of adhesion and activation steps, known as the "adhesion cascade." 1 Thus, selectins are largely responsible for initial tethering of flowing PMNs to endothelium and also mediate subsequent PMN rolling on the endothelial surface. Activation of rolling PMNs leads to leukocyte arrest via modulation of the affinity and avidity of ␤ 2 integrins, with LFA-1 (CD11a/CD18) acting primarily to slow rolling and to promote arrest, and Mac-1 (CD11b/CD18) acting to stabilize adhesion. [2][3][4][5] The capacity of endothelial cells (ECs) to support these interactions with PMNs is stimulated by cytokines such as TNF␣ and IL-1␤, which induce expression of a large number of adhesion molecules, chemottractant, and other proinflammatory genes, including E-selectin, chemokines (eg, IL-8), and ICAM-1. 6,7 Antibodies that react with the surface of vascular endothelial cells (antiendothelial cell antibodies, AECAs) are found in a variety of diseases associated with vascular injury, including systemic lupus erythematosus (SLE), systemic sclerosis, Takayasu arteritis, Wegener granulomatosis, Behçets syndrome, and transplant arteriosclerosis, 8,9 A number of mechanisms have been proposed whereby IgG binding to ECs may exert pathogenic effects, including the induction of EC inflammatory activation and thrombogenicity, the stimulation of leukocyte free-radical production and cellular cytotoxicity, and the induction of EC apoptosis. [10][11][12][13][14] Interactions between circulating human PMNs and immune complexes are mediated via 2 low-affinity Fc␥ receptors, Fc␥RIIa (CD32a) and Fc␥RIIIb (CD16b), which are both thought to form homodimers and have distinct membrane-anchoring and -signaling capacities. [15][16][17][18][19] The cytoplasmic domain of Fc␥RIIa has a specialized immunoreceptor tyrosine-based activ...

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Crystal Structure of the Extracellular Domain of a Human FcγRIII

Cited by 95 publications

References 32 publications

Recognition and functional activation of the human IgA receptor (FcαRI) by C-reactive protein

Recognition and functional activation of the human IgA receptor (FcαRI) by C-reactive protein

The Structure of a Human Type III Fcγ Receptor in Complex with Fc

Antiendothelial cell antibodies mediate enhanced leukocyte adhesion to cytokine-activated endothelial cells through a novel mechanism requiring cooperation between FcγRIIa and CXCR1/2

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