Review
Human C-reactive protein: expression, structure, and function

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Abstract

C-reactive protein (CRP) is an acute-phase protein featuring a homopentameric structure and Ca-binding specificity for phosphocholine (PCh). Expression of CRP is regulated mainly at the transcriptional level with interleukin-6 being the principal inducer of the gene during the acute phase. The crystal structure of CRP has been determined and the topology and chemical composition of its ligand-binding site determined. The wide distribution of PCh in polysaccharides of pathogens and in cellular membranes allows CRP to recognize a range of pathogenic targets as well as membranes of damaged and necrotic host cells. CRP bound to a multivalent ligand can efficiently initiate the assembly of a C3 convertase through the classical pathway and thus decorate the surface of the ligand with opsonic complement fragments. However, the protein does not favor the formation of a C5 convertase and therefore, CRP-initiated complement activation does not mediate acute inflammatory reactions and membrane damage. CRP also interacts with Fc receptors on phagocytic cells and acts as an opsonin. Other CRP-initiated signals through interactions with neutrophil Fc receptors have an overall anti-inflammatory effect. Thus, the main biological function of CRP appears to be host defense against bacterial pathogens and clearance of apoptotic and necrotic cells. Protection from lethal bacterial infection, from complement-induced alveolitis, and from endotoxemia has been confirmed in vivo using transgenic mice. Additional functions, including participation in atherogenesis and pathogenesis of myocardial injury after myocardial infarction have been reported. However, the weight of the evidence is that CRP like other acute-phase proteins is a component first line of innate host defense.

Introduction

C-reactive protein (CRP) is a member of the phylogenetically ancient and highly conserved ‘pentraxin’ family of proteins, which also includes serum amyloid P component (SAP), a constituent of all amyloid deposits. In man and other animal species, CRP is a major acute-phase plasma protein displaying rapid and pronounced rise of its serum concentration in response to infection or tissue injury. CRP has Ca2+-dependent binding specificity for phosphocholine (PCh), a constituent of many bacterial and fungal polysaccharides and of most biological cell membranes (Volanakis and Kaplan, 1971). Indeed, CRP was discovered and named because of its reactivity with the PCh residues of C-polysaccharide (PnC), the teichoic acid of Streptococcus pneumoniae (Tillett and Francis, 1930). CRP also binds certain nuclear constituents, which do not contain PCh, such as small ribonucleoprotein particles (Du Clos, 1989, Pepys et al., 1994). Ligand-complexed CRP is recognized by C1q and efficiently activates the classical pathway of human complement (Kaplan and Volanakis, 1974, Volanakis, 1982a). Complexed CRP can also elicit responses from phagocytic cells through binding to the FcγRI and FcγRIIa receptors (Marnell et al., 1995, Bharadwaj et al., 1999). Its ability to recognize pathogens and to mediate their elimination by recruiting the complement system and phagocytic cells makes CRP an important constituent of the first line of innate host defense. Furthermore, the protein appears to play a role in the clearance of apoptotic and necrotic host cells, thus contributing to restoration of normal structure and function of injured tissues. Like other elements of immunity, CRP perhaps has not only protective, but also potentially harmful effects. Thus, recently CRP has been implicated in atherogenesis (Torzewski et al., 2000, Zwaka et al., 2001) and in the mediation of tissue damage in acute myocardial infarction (Griselli et al., 1999).

Section snippets

Regulation of expression

The swift rise of its serum concentration during the acute phase, the magnitude of the response approaching 1000-fold increase within 24–48 h, and the equally quick return to the very low normal concentration of a few μg/ml are the most impressive biologic characteristics of CRP. Expression of CRP is regulated mainly at the transcriptional level, but post-transcriptional mechanisms also play a significant role. The CRP gene has been mapped to human chromosome 1, between 1q21 and 1q23. It

Structure

The structure of CRP has been determined by X-ray crystallography at 3 Å resolution (Shrive et al., 1996, Thompson et al., 1999). Like SAP, the other pentraxin of known structure (Emsley et al., 1994), CRP consists of five noncovalently associated protomers arranged symmetrically around a central pore. The overall dimensions of the CRP pentamer are about 102 Å outside diameter with a central pore diameter of 30 Å and a protomer diameter of 36 Å. The protomer consists of 206 amino acids folded

Function

The main biologic function of CRP is determined by its ability to recognize pathogens and damaged cells of the host and to mediate their elimination by recruiting the complement system and phagocytic cells. PCh, the principal CRP ligand, is widely distributed in teichoic acids, capsular carbohydrates, and lipopolysaccharides of bacteria and other micro-organisms. Its presence has been reported in S. pneumoniae (Brundish and Baddiley, 1968), Haemophilus influenzae (Weiser et al., 1997),

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