The Interaction of FcαRI with IgA and Its Implications for Ligand Binding by Immunoreceptors of the Leukocyte Receptor Cluster

Wines, Bruce D.; Sardjono, Caroline T.; Trist, H H; Lay, Chan-Sien; Hogarth, P. Mark

doi:10.4049/jimmunol.166.3.1781

Cited by 80 publications

(93 citation statements)

References 48 publications

(44 reference statements)

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“…In contrast, whereas the SSL7 molecules cover most of the C␣3 domains, the Fc␣RI grasps the Fc like bent fingers (Fig. 5B), which is perhaps a steric requirement of this receptor normally being anchored in, and ''standing up'' from, the cellular membrane (24,28).…”

Section: Mutagenesis Confirms the Role Of Key Ssl7 Residues In Bindinmentioning

confidence: 99%

Structural basis for evasion of IgA immunity by Staphylococcus aureus revealed in the complex of SSL7 with Fc of human IgA1

Ramsland

Willoughby

Trist

et al. 2007

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

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104

102

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Infection by Staphylococcus aureus can result in severe conditions such as septicemia, toxic shock, pneumonia, and endocarditis with antibiotic resistance and persistent nasal carriage in normal individuals being key drivers of the medical impact of this virulent pathogen. In both virulent infection and nasal colonization, S. aureus encounters the host immune system and produces a wide array of factors that frustrate host immunity. One in particular, the prototypical staphylococcal superantigen-like protein SSL7, potently binds IgA and C5, thereby inhibiting immune responses dependent on these major immune mediators. We report here the three-dimensional structure of the complex of SSL7 with Fc of human IgA1 at 3.2 Å resolution. Two SSL7 molecules interact with the Fc (one per heavy chain) primarily at the junction between the C␣2 and C␣3 domains. The binding site on each IgA chain is extensive, with SSL7 shielding most of the lateral surface of the C␣3 domain. However, the SSL7 molecules are positioned such that they should allow binding to secretory IgA. The key IgA residues interacting with SSL7 are also bound by the leukocyte IgA receptor, Fc␣RI (CD89), thereby explaining how SSL7 potently inhibits IgAdependent cellular effector functions mediated by Fc␣RI, such as phagocytosis, degranulation, and respiratory burst. Thus, the ability of S. aureus to subvert IgA-mediated immunity is likely to facilitate survival in mucosal environments such as the nasal passage and may contribute to systemic infections.Staphylococcus aureus is an important human pathogen causing conditions ranging from minor superficial skin infections to life-threatening syndromes, including sepsis, toxic shock syndrome, osteomyelitis, pneumonitis, and endocarditis. It is carried without symptoms in at least 20% of individuals (1, 2). The emergence in the 1960s of pandemic penicillin-resistant S. aureus has been followed by a variety of hospital-associated and community-associated methicillin-resistant strains (HA-and CA-MRSA) (2, 3). The increased prevalence of MRSA infections and corresponding rise in life-threatening syndromes have made it imperative to elucidate the mechanisms of pathogenesis for S. aureus. The interaction between S. aureus and the host is complex and is mediated by an array of bacterial proteins that both mediate the various pathologies and modify the immune system of the host (4-10).SSL7 (formerly named SET1) is the first described member of a new family of putative S. aureus toxins, the staphylococcal superantigen-like (SSL) proteins (11, 12), related to the staphylococcal enterotoxins (SEs) or superantigens (13). The SSL proteins have Ϸ30% sequence identity with toxic shock syndrome 1 (TSST-1) and 25% or less identity with other SEs. Despite the sequence differences, the SSL proteins have a typical SE tertiary structure consisting of a distinct oligonucleotide/oligosaccharide binding (OB-fold) linked to a ␤-grasp domain (14 -16).Similar to the se genes, the ssl genes are located in a pathogenicity island (SaPIn2) and ...

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Section: Mutagenesis Confirms the Role Of Key Ssl7 Residues In Bindinmentioning

confidence: 99%

Structural basis for evasion of IgA immunity by Staphylococcus aureus revealed in the complex of SSL7 with Fc of human IgA1

Ramsland

Willoughby

Trist

et al. 2007

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

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104

102

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“…The receptor binds IgA1 and IgA2 with an equal affinity (5). A number of residues including Tyr 35 (6,7).…”

mentioning

confidence: 99%

Crystal Structure of the Ectodomain of Human FcαRI

Ding

Yang

et al. 2003

Journal of Biological Chemistry

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Human Fc␣RI (CD89) is the receptor specific for IgA, an immunoglobulin that is abundant in mucosa and is also found in high concentrations in serum. Although Fc␣RI is an immunoglobulin Fc receptor (FcR), it differs in many ways from FcRs for other immunoglobulin classes. The genes of most FcRs are located on chromosome 1 at 1q21-23, whereas Fc␣RI is on chromosome 19, at 19q13.4, a region called the leukocyte receptor complex, because it is clustered with several leukocyte receptor families including killer cell inhibitory receptors (KIRs) and leukocyte Ig-like receptors (LIRs). The amino acid sequence of Fc␣RI shares only 20% homology with other FcRs but it has around 35% homology with its neighboring LIRs and KIRs. In this work, we analyzed the crystal structure of the ectodomain of Fc␣RI and examined structure similarities between Fc␣RI and KIR2DL1, KIR2DL2 and LIR-1. Our data show that Fc␣RI, KIRs, and LIRs share a common hydrophobic core in their interdomain interface, and Fc␣RI is evolutionally closer to LIR than KIR.In humans, IgA is the most abundant immunoglobulin in secretions, and it constitutes about 20% of the immunoglobulin pool in serum (1, 2). Since its turnover rate is faster than other immunoglobulins, the daily production of IgA exceeds all other immunoglobulins combined (3). Undoubtedly, IgA should to play important roles in immune defense against invaded pathogens.Five types of IgA receptors have been recognized so far. They are Fc␣RI (CD89), the polymeric Ig receptor, Fc␣/R, the transferrin receptor, and the asialoglycoprotein receptor (1). Among them, Fc␣RI is the only one that specifically binds IgA. On ligation of IgA complexed with antigens, Fc␣RI is able to mediate various cellular responses including phagocytosis, antibody-dependent cell cytotoxicity, oxidative bursts, and release of inflammatory mediators (1).Fc␣RI belongs to the immunoglobulin superfamily and contains an extracellular region of 206 amino acids, a transmembrane domain of 19 amino acids and a cytoplasmic region of 41 amino acids (4 Although Fc␣RI is an immunoglobulin Fc receptor (FcR), 1 it differs in many ways with FcRs for other immunoglobulin classes. IgG receptor Fc␥RIII and IgE receptor Fc⑀RI bind antibodies in the near hinge regions and form 1:1 complexes (8, 9), whereas Fc␣RI binds the C H 2-C H 3 interface of Fc␣ (10, 11) and preferably forms 2:1 complex with a single Fc␣ homodimer (12). It has been reported that Fc␥Rs and Fc⑀RI use their membrane proximal-domain and linker region binds immunoglobulin (8, 9, 13, 14), whereas Fc␣RI uses its membrane-distal domain EC1 to bind IgA (15).The genes of most FcRs are located in chromosome 1 at 1q21-23 (16), whereas Fc␣RI is in chromosome 19, at 19q13.4 (17, 18), a region called the leukocyte receptor complex because it is clustered with several leukocyte receptor families including killer cell inhibitory receptors (KIRs) and leukocyte Ig-like receptors (LIR/LILR/ILTs) (17, 18). The amino acid sequence of Fc␣RI shares only 20% homology with other FcRs, but it has around...

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“…FcαRI are such receptors. They bind monomeric IgA with a moderate affinity and dimeric IgA with a high avidity (Wines et al, 2001). FcαRI are encoded by genes of the Leukocyte Receptor Complex, on chromosome 19.…”

Section: Promiscuous Negative Regulation Of Activating Fcrs By Fcαrimentioning

confidence: 99%

Negative Signaling in Fc Receptor Complexes

Daëron

Lesourne

2006

Advances in Immunology

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Cell activation results from the transient displacement of an active balance between positive and negative signaling. This displacement depends in part on the engagement of cell surface receptors by extracellular ligands. Among these are Receptors for the Fc portion of immunoglobulins (FcRs). FcRs are widely expressed by cells of hematopoietic orign. When binding antibodies, FcRs provide these cells with immunoreceptors capable of triggering numerous biological responses in response to specific antigen. FcR-dependent cell activation is regulated by negative signals which are generated together with positive signals within signalosomes that form upon FcR engagement. Many molecules involved in positive signaling, including the FcRβ subunit, the src kinase lyn, the cytosolic adapter Grb2, the transmembrane adapters LAT and NTAL, are indeed also involved in negative signaling. A major player in negative regulation of FcR signaling is the inositol 5-phosphatase SHIP1. Several layers of negative regulation operate sequentially as FcRs are engaged by extracellular ligands of increasing valency. A background protein tyrosine phosphatasedependent negative regulation maintains cells in a « resting » state. SHIP1-dependent negative regulation can be detected as soon as high-affinity FcRs are occupied by antibodies in the absence of antigen. It increases when activating FcRs are engaged by multivalent ligands and, further when FcR aggregation increases, accounting for the bell-shaped dose-response curve observed in excess of ligand. Finally, F-actin skeleton-associated high-molecular weight SHIP1, recruited to phopshorylated ITIMs, concentrates in signaling complexes when activating FcRs are coengaged with inhibitory FcRs by immune complexes. Based on these data, activating and inhibitory FcRs could be used for new therapeutic approaches of immune disorders.

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The Interaction of FcαRI with IgA and Its Implications for Ligand Binding by Immunoreceptors of the Leukocyte Receptor Cluster

Cited by 80 publications

References 48 publications

Structural basis for evasion of IgA immunity by Staphylococcus aureus revealed in the complex of SSL7 with Fc of human IgA1

Structural basis for evasion of IgA immunity by Staphylococcus aureus revealed in the complex of SSL7 with Fc of human IgA1

Crystal Structure of the Ectodomain of Human FcαRI

Negative Signaling in Fc Receptor Complexes

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