Structural basis of ligand specificity in the human pentraxins, C-reactive protein and serum amyloid P component

Laboratory of Protein Crystallography, Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London Medical School, Rowland Hill Street, London NW3 2PF, UK.
Journal of Molecular Recognition (Impact Factor: 2.15). 03/2011; 24(2):371-7. DOI: 10.1002/jmr.1090
Source: PubMed


The normal physiological roles of the phylogenetically conserved human plasma proteins C-reactive protein (CRP) and serum amyloid P component (SAP) are not known. Novel drugs targeting their ligand specificities are in clinical development as both proteins have significant pathophysiological effects, SAP in promoting amyloidosis and CRP in exacerbating ischemic injury. Both proteins bind to phosphoethanolamine and we show here that, under physiological conditions, phosphoethanolamine is bound with higher affinity by human SAP than by human CRP. An explanation is provided by X-ray crystal structures that show SAP residue Tyr74 allowing additional hydrophobic protein-ligand interactions compared with the equivalent Thr76 of CRP. Docking simulations show many more low energy positions for phosphoethanolamine bound by CRP than by SAP and are consistent with the crystallographic and functional binding results. These fundamental observations on structure-activity relationships will aid the design of improved pentraxin targeting drugs.

Download full-text


Available from: Halina Mikolajek,
  • Source
    • "Between the N-terminal 9–10 Calx-beta motifs, there are about 200 amino acids forming a pentraxin (PTX) domain with a distinctive flattened β-jellyroll structure (Fig. 1a, b). Members of pentraxin family include C-reactive protein and Serum amyloid P component, which could mediate acute immunological responses or extracellular proteins-receptor interactions (Lu et al. 2008; Mikolajek et al. 2011). About 2,000 amino acids after the PTX domain, an EAR (epilepsy associated repeats) domain is inserted between 22 and 23 Calx-beta motifs (Fig. 1a, b). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The very large G protein coupled receptor (Vlgr1) is a member of adhesion receptors or large N-terminal family B-7 transmembrane helixes (LNB7TM) receptors within the seven trans-membrane receptor superfamily. Vlgr1 is the largest GPCR identified to date; its mRNA spans 19 kb and encodes 6,300 amino acids. Vlgr1 is a core component of ankle-link complex in inner ear hair cells. Knock-out and mutation mouse models show that loss of Vlgr1 function leads to abnormal stereociliary development and hearing loss, indicating crucial roles of Vlgr1 in hearing transduction or auditory system development. Over the past 10 or so years, human genetics data suggested that Vlgr1 mutations cause Usher syndromes and seizures. Although significant progresses have been made, the details of Vlgr1's function in hair cells, its signaling cascade, and the mechanisms underlying causative effects of Vlgr1 mutations in human diseases remain elusive and ask for further investigation.
    Journal of Molecular Neuroscience 11/2012; 50(1). DOI:10.1007/s12031-012-9911-5 · 2.34 Impact Factor
  • Source
    • "The other face, designated B, contains a ligand-binding concave face. The ligand-binding site consists of several residues that form a hydrophobic pocket and two Ca 2+ ions [14] [15]. The contact domain between subunits comprises the open-core end of the two-layered b sheet of one protomer and the N-and C-terminal strands of another [16]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The short pentraxins C-reactive protein (CRP) and serum amyloid P component (SAP) constitute a group of innate immune receptors that trigger immune activation by detecting molecules of the microbial cell wall. Here, we examined the evolution of short pentraxins in Murinae lineages. By molecular evolutionary analysis, CRP and SAP have been experiencing rapid diversification, driven by adaptive selection. Further, our protein modeling demonstrates that adaptively selected amino acids lie in the ligand-binding region and contact region between subunits. Our findings suggest that rapid diversification of these regions could contribute to the determinants of recognizing specificity and the interaction between subunits.
    FEBS letters 02/2012; 586(6):798-803. DOI:10.1016/j.febslet.2012.01.048 · 3.17 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: C-reactive protein (CRP) is a blood marker of inflammation and a hallmark of the acute-phase response. Its elevation bears negative prognostic implications for many conditions and it has also been shown to be a nonspecific predictor of long-term risk of cerebrovascular disease (CVD) in several populations, while elevations of CRP associated with the major acute-phase response following ischemic or hemorrhagic stroke are associated with death and vascular complications. High-sensitivity assays that accurately measure levels of CRP have been proposed for use in risk assessment for CVD and as a prognostic marker after an acute event, although the pathogenic and clinical significance of these associations is controversial. In this article, we critically review the literature in narrative format and describe major epidemiological studies, novel experiments and possible future developments that may inform the debate. In our discussion, we will distinguish the different pathophysiological roles of high circulating CRP concentrations in individuals with acute stroke from the modestly and persistently increased levels of CRP concentration in generally healthy subjects. However, before any clinical application is possible, a critical appraisal of the strengths and deficiencies of the accumulated evidence is required, both to consider the current state of knowledge and to inform the design of future research.
    Expert Review of Cardiovascular Therapy 12/2011; 9(12):1565-84. DOI:10.1586/erc.11.159
Show more