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

Lu, Jinghua; Marjon, Kristopher D.; Marnell, Lorraine L.; Wang, Ruipeng; Mold, Carolyn; Clos, Terry W. Du; Sun, Peter D.

doi:10.1073/pnas.1018369108

Cited by 69 publications

(69 citation statements)

References 33 publications

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“…Both the A and C subunits of SAP use their ridge helix and C-terminus to contact topologically identical D1-and D2-domains of FcgRIIA, respectively. Compared to FcgRIIA, FcaRI also contains two Ig-like domains except the D1-D2 orientation is flipped by almost 180 , 21,24 leaving the possibility that the receptor may bind to pentraxins in a similar way as FcgRIIA. A model of CRP binding to FcaRI, generated based on the SAP-FcgRIIA cocrystal structure, suggests regions of the IgA receptor that may be involved in pentraxin interaction.…”

Section: Design Of Fcari Mutationsmentioning

confidence: 99%

“…Given the fact that FcgRs use topologically identical secondary structures on the receptor D1 and D2 domains to contact with two diagonally positioned subunits of pentraxins, a docking model of FcaRI-pentraxin interaction was generated. 21 In the current work, we mutated residues in FcaRI that lie at the contact region as predicted by the model and tested the binding of these mutants to CRP, SAP, and IgA. The results showed that the pentraxin recognition residues of FcaRI primarily reside in the receptor D1 domain in a region shared with the IgA-binding site.…”

Section: Introductionmentioning

confidence: 99%

“…A model of CRP binding to FcaRI, generated based on the SAP-FcgRIIA cocrystal structure, suggests regions of the IgA receptor that may be involved in pentraxin interaction. 21 To investigate the individual contributions of these structural elements and map the binding interface of FcaRI-pentraxin recognition, we designed six alanine cluster or single mutations [ Fig. 1(B,C)].…”

Section: Design Of Fcari Mutationsmentioning

confidence: 99%

“…18 More recently, we identified FcaRI as another cell surface receptor for pentraxins. 21 FcaRI (CD89) is the major receptor for IgA in humans and no murine counterpart is known. 22,23 It is also a transmembrane protein with two extracellular domains and a short intracellular domain, which is associated with the FcRg-chain.…”

Section: Introductionmentioning

confidence: 99%

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Pentraxins and IgA share a binding hot‐spot on FcαRI

Marjon

Mold

et al. 2014

Protein Science

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The pentraxins, C-reactive protein (CRP), and serum amyloid P component (SAP) have previously been shown to function as innate opsonins through interactions with Fcc receptors. The molecular details of these interactions were elucidated by the crystal structure of SAP in complex with FccRIIA. More recently, pentraxins were shown to bind and activate FcaRI (CD89), the receptor for IgA. Here, we used mutations of the receptor based on a docking model to further examine pentraxin recognition by FcaRI. The solution binding of pentraxins to six FcaRI alanine cluster mutants revealed that mutations Y35A and R82A, on the C-and F-strands of the D1 domain, respectively, markedly reduced receptor binding to CRP and SAP. These residues are in the IgAbinding site of the receptor, and thus, significantly affected receptor binding to IgA. The shared pentraxin and IgA-binding site on FcaRI is further supported by the results of a solution binding competition assay. In addition to the IgA-binding site, pentraxins appear to interact with a broader region of the receptor as the mutation in the C 0 -strand (R48A/E49A) enhanced pentraxin binding. Unlike Fcc receptors, the H129A/I130A and R178A mutations on the BC-and FG-loops of D2 domain, respectively, had little effect on FcaRI binding to the pentraxins. In conclusion, our data suggest that the pentraxins recognize a similar site on FcaRI as IgA.

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Section: Design Of Fcari Mutationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Design Of Fcari Mutationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pentraxins and IgA share a binding hot‐spot on FcαRI

Marjon

Mold

et al. 2014

Protein Science

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“…FcαR [6], SR-A [7] and LOX-1 [8], thus giving CRP the potential to modulate the responses of immune and vascular cells. These characteristics lead to the consensus that CRP is an important component of the host defense and inflammation [1][2][3], despite the fact that the actual function of CRP remains to be clearly defined in an appropriate animal model [1,9,10].…”

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confidence: 99%

Regulated conformation changes in C-reactive protein orchestrate its role in atherogenesis

2012

Chin. Sci. Bull.

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C-reactive protein (CRP) is a prototypic human acute phase reactant composed of five identical subunits. Emerging evidence indicates that CRP is not merely a predictor of cardiovascular disease, but may also be a direct mediator. However, the diverse and sometimes contradictory activities of CRP have considerably hampered the attempts to define the exact role of CRP in atherogenesis. Here, we review the multiple layers of regulation of CRP's structure and function, highlighting how local inflammation conditions, such as the abundance of damaged cell membranes and redox homeostasis, can tip the balance of the pro-and antiinflammatory activities of CRP. We propose that the highly controlled interplay between different structural conformations of CRP underlies its intrinsic property as a fine modulator of inflammation and atherogenesis. C-reactive protein, inflammation, atherosclerosis, redox Citation:Ma X, Ji S R, Wu Y. Regulated conformation changes in C-reactive protein orchestrate its role in atherogenesis.

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Pentraxins

Mold

Sun

Clos

2012

Encyclopedia of Life Sciences

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The pentraxin family of proteins is characterised by sequence and structural homology and calcium‐dependent ligand binding. The human pentraxins are C‐reactive protein (CRP) and serum amyloid P component (SAP), the former of which is a strong acute phase protein. The activities of CRP and SAP are mediated through the classical complement pathway and through activation of Fc receptors (FcRs). Pentraxins are pattern recognition molecules that play important roles in host defence and control of inflammation. Measurement of CRP in blood has been used to monitor inflammation and infection and more recently to predict cardiovascular disease. Recent studies suggest that each of the pentraxins plays a role in the regulation of inflammation and tissue fibrosis. Knockout and transgenic models suggest that these effects are due to interaction with FcRs on macrophages and dendritic cells. Ongoing laboratory studies and clinical trials suggest that pentraxins may have therapeutic benefits. Key Concepts: Pentraxins form a family of proteins based on structural homology and calcium‐dependent ligand binding. Pentraxins are serum proteins that are important in host defence and regulation of the inflammatory response. The functional activities of CRP and SAP are mediated by complement activation and by interaction with Fc receptors on leucocytes. Structurally pentraxins are planar pentamers with five calcium‐dependent ligand‐binding sites on one face and a binding site for a single Fc receptor on the opposite face. CRP and SAP are the two members of the pentraxin family found in most animals. Human CRP is a strong acute phase reactant made in the liver in response to tissue injury or infection. CRP is often used to monitor inflammation or infection because of its rapid synthesis and clearance. CRP has anti‐inflammatory activity mediated through Fcγ receptors in a number of mouse autoimmune models and in endotoxin shock. SAP inhibits fibrocyte differentiation and prevents fibrosis in pulmonary and renal models. Genetic polymorphisms in noncoding regions of the CRP gene determine baseline levels of CRP and are the risk factors for systemic lupus erythematosus, but not cardiovascular disease.

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

Cited by 69 publications

References 33 publications

Pentraxins and IgA share a binding hot‐spot on FcαRI

Pentraxins and IgA share a binding hot‐spot on FcαRI

Regulated conformation changes in C-reactive protein orchestrate its role in atherogenesis

Pentraxins

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