The binding of C-reactive protein, in the presence of phosphoethanolamine, to low-density lipoproteins is due to phosphoethanolamine-generated acidic pH

Singh, Sanjay K.; Hammond, David J.; Beeler, Bradley W.; Agrawal, Alok

doi:10.1016/j.cca.2009.08.013

Cited by 13 publications

(16 citation statements)

References 3 publications

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“…Proteins-We reported previously that the binding of CRP to ox-LDL at acidic pH was not due to its specificity for binding to ox-LDL but due to its specificity for binding to immobilized, modified, and conformationally altered proteins, irrespective of the identity of the protein (5,6). Therefore, we investigated the binding activity of E42Q CRP at acidic pH for a few immobilized proteins other than ox-LDL.…”

Section: E42q Crp Has Higher Avidity Than Wt Crp For Binding To a Varmentioning

confidence: 99%

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Exposing a Hidden Functional Site of C-reactive Protein by Site-directed Mutagenesis

Singh

Thirumalai

Hammond

et al. 2012

Journal of Biological Chemistry

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Background:The functions of C-reactive protein (CRP) in the extracellular matrix at the sites of inflammation are unknown. Results: Mutation of just one amino acid in CRP (E42Q) expands its ligand-binding capacity. Conclusion: Some functions of CRP depend upon its inflammation-induced structural configuration. Significance: Investigations using E42Q-CRP in animal models of inflammatory diseases may establish its therapeutic potential, the functions of CRP, and a CRP-targeting strategy.

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Section: E42q Crp Has Higher Avidity Than Wt Crp For Binding To a Varmentioning

confidence: 99%

“…We have shown previously that pH regulates the ligand-binding function of CRP. Acidic pH transforms native pentameric CRP into another pentameric configuration that recognizes immobilized ligands made up of conformationally altered proteins (5,6).…”

Section: C-reactive Protein (Crp)mentioning

confidence: 99%

Exposing a Hidden Functional Site of C-reactive Protein by Site-directed Mutagenesis

Singh

Thirumalai

Hammond

et al. 2012

Journal of Biological Chemistry

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Section: C-reactive Protein (Crp)mentioning

confidence: 99%

“…The ligand recognition function of native pentameric CRP is to bind, in a Ca 2ϩ -dependent manner, to phosphocholine (PCh)-containing substances, such as pneumococcal cell wall C-polysaccharide (PnC), necrotic cells, platelet-activating factor, PCh-containing molecules on the surface of parasites, enzymatically modified LDL, and oxidized LDL (ox-LDL) if the oxidation was sufficient to expose the PCh groups present in LDL (3-10). Under certain conditions, such as in an acidic pH buffer, CRP adapts a different pentameric configuration that exposes a hidden ligandbinding site for non-PCh ligands and that enables CRP to bind to immobilized, denatured, and aggregated proteins, irrespective of the identity of the native protein (11)(12)(13) , respectively, also converts CRP into molecules that bind to a variety of immobilized, denatured, and aggregated proteins (11,14).CRP is a plasma protein that is present at sites of inflammation such as necrotic areas in local inflammatory lesions, synovium of patients with rheumatoid arthritis, inflammatory lesions of experimental allergic encephalomyelitis, inflammatory and arterial atherosclerotic lesions, and neurofibrillary tangles of Alzheimer's disease (15)(16)(17)(18)(19)(20)(21)(22). When CRP is present at sites of inflammation, it is exposed to an inflammatory microenvironment.…”

mentioning

confidence: 99%

“…Under certain conditions, such as in an acidic pH buffer, CRP adapts a different pentameric configuration that exposes a hidden ligandbinding site for non-PCh ligands and that enables CRP to bind to immobilized, denatured, and aggregated proteins, irrespective of the identity of the native protein (11)(12)(13). Mutagenesis of Glu 42 or Pro 115 , amino acids in the intersubunit contact region in pentameric CRP, to Gln 42 and Ala…”

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confidence: 99%

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Functional Transformation of C-reactive Protein by Hydrogen Peroxide

Singh

Thirumalai

Pathak

et al. 2017

Journal of Biological Chemistry

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Edited by Luke O'NeillC-reactive protein (CRP) is present at sites of inflammation including amyloid plaques, atherosclerotic lesions, and arthritic joints. CRP, in its native pentameric structural conformation, binds to cells and molecules that have exposed phosphocholine (PCh) groups. CRP, in its non-native pentameric structural conformation, binds to a variety of deposited, denatured, and aggregated proteins, in addition to binding to PCh-containing substances. In this study, we investigated the effects of H 2 O 2 , a prototypical reactive oxygen species that is also present at sites of inflammation, on the ligand recognition function of CRP. is a biological modifier of the structure and ligand recognition function of CRP. Overall, the data suggest that the ligand recognition function of CRP is dependent on the presence of an inflammatory microenvironment. We hypothesize that one of the functions of CRP at sites of inflammation is to sense the inflammatory microenvironment, change its own structure in response but remain pentameric, and then bind to pathogenic proteins deposited at those sites. C-reactive protein (CRP)3 is a pentameric molecule made up of five non-covalently associated, identical subunits arranged symmetrically around a central pore (1, 2). The ligand recognition function of native pentameric CRP is to bind, in a Ca 2ϩ -dependent manner, to phosphocholine (PCh)-containing substances, such as pneumococcal cell wall C-polysaccharide (PnC), necrotic cells, platelet-activating factor, PCh-containing molecules on the surface of parasites, enzymatically modified LDL, and oxidized LDL (ox-LDL) if the oxidation was sufficient to expose the PCh groups present in LDL (3-10). Under certain conditions, such as in an acidic pH buffer, CRP adapts a different pentameric configuration that exposes a hidden ligandbinding site for non-PCh ligands and that enables CRP to bind to immobilized, denatured, and aggregated proteins, irrespective of the identity of the native protein (11)(12)(13) , respectively, also converts CRP into molecules that bind to a variety of immobilized, denatured, and aggregated proteins (11,14).CRP is a plasma protein that is present at sites of inflammation such as necrotic areas in local inflammatory lesions, synovium of patients with rheumatoid arthritis, inflammatory lesions of experimental allergic encephalomyelitis, inflammatory and arterial atherosclerotic lesions, and neurofibrillary tangles of Alzheimer's disease (15)(16)(17)(18)(19)(20)(21)(22). When CRP is present at sites of inflammation, it is exposed to an inflammatory microenvironment. The microenvironment at sites of inflammation including arterial lesions in atherosclerosis, inflammation in the eye and the sites of bacterial infection, is characterized by acidic pH, hypoxia, and increased O 2 and energy demand, which result in the production of reactive oxygen species (ROS), including H 2 O 2 , and subsequent dysregulation of the extracellular redox environment, which is known to cause modifications in the proteins prese...

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Computational Analysis of C-Reactive Protein for Assessment of Molecular Dynamics and Interaction Properties

Chakraborty

Agrawal

2013

Cell Biochem Biophys

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Serum C-reactive protein (CRP) is used as a marker of inflammation in several diseases including autoimmune disease and cardiovascular disease. CRP, a member of the pentraxin family, is comprised of five identical subunits. CRP has diverse ligand-binding properties which depend upon different structural states of CRP. However, little is known about the molecular dynamics and interaction properties of CRP. In this study, we used SAPS, SCRATCH protein predictor, PDBsum, ConSurf, ProtScale, Drawhca, ASAView, SCide and SRide server and performed comprehensive analyses of molecular dynamics, protein–protein and residue–residue interactions of CRP. We used 1GNH.pdb file for the crystal structure of human CRP which generated two pentamers (ABCDE and FGHIJ). The number of residues involved in residue–residue interactions between A–B, B–C, C–D, D–E, F–G, G–H, H–I, I–J, A–E and F–J subunits were 12, 11, 10, 11, 12, 11, 10, 11, 10 and 10, respectively. Fifteen antiparallel β sheets were involved in β-sheet topology, and five β hairpins were involved in forming the secondary structure. Analysis of hydrophobic segment distribution revealed deviations in surface hydrophobicity at different cavities present in CRP. Approximately 33 % of all residues were involved in the stabilization centers. We show that the bioinformatics tools can provide a rapid method to predict molecular dynamics and interaction properties of CRP. Our prediction of molecular dynamics and interaction properties of CRP combined with the modeling data based on the known 3D structure of CRP is helpful in designing stable forms of CRP mutants for structure–function studies of CRP and may facilitate in silico drug design for therapeutic targeting of CRP.

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The binding of C-reactive protein, in the presence of phosphoethanolamine, to low-density lipoproteins is due to phosphoethanolamine-generated acidic pH

Cited by 13 publications

References 3 publications

Exposing a Hidden Functional Site of C-reactive Protein by Site-directed Mutagenesis

Exposing a Hidden Functional Site of C-reactive Protein by Site-directed Mutagenesis

Functional Transformation of C-reactive Protein by Hydrogen Peroxide

Computational Analysis of C-Reactive Protein for Assessment of Molecular Dynamics and Interaction Properties

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