C-Reactive Protein Sequences
C-reactive protein (CRP) is an acute phase protein. It is phylogenetically ancient and - with serum amyloid P - belongs to proteins named as "pentraxin".
CRP was discovered in Oswald Avery's laboratory during the course of studies of patients with Streptococcus pneumoniae infection. Sera obtained from these patients during the early, acute phase of the illness were found to contain a protein that could precipitate the “C” polysaccharide derived from the pneumococcal cell wall1.
CRP belongs to the pentraxin family of calcium-dependent ligand-binding plasma proteins, the other member of which in humans is serum amyloid P component (SAP). The human CRP molecule (Mr 115,135) is composed of five identical nonglycosylated polypeptide subunits (Mr 23,027), each containing 206 amino acid residues. The protomers are noncovalently associated in an annular configuration with cyclic pentameric symmetry. Each protomer has the characteristic "lectin fold," composed of a two-layered ß sheet with flattened jellyroll topology. The ligand-binding site, composed of loops with two calcium ions bound 4 Å apart by protein side-chains, is located on the concave face. The other face carries a single a helix2.
Mode of Action
Human CRP binds with highest affinity to phosphocholine residues, but it also binds to a variety of other autologous and extrinsic ligands, and it aggregates or precipitates the cellular, particulate, or molecular structures bearing these ligands. Autologous ligands include native and modified plasma lipoproteins, damaged cell membranes, a number of different phospholipids and related compounds, small nuclear ribonucleoprotein particles, and apoptotic cells. Extrinsic ligands include many glycan, phospholipid, and other constituents of microorganisms, such as capsular and somatic components of bacteria, fungi, and parasites, as well as plant products. When aggregated or bound to macromolecular ligands, human CRP is recognized by C1q and potently activates the classical complement pathway, engaging C3, the main adhesion molecule of the complement system, and the terminal membrane attack complex, C5–C9. Bound CRP may also provide secondary binding sites for factor H and thereby regulate alternative-pathway amplification and C5 convertases3.
CRP, the Metabolic Syndrome, and Risk of Incident Cardiovascular Events: The metabolic syndrome describes a high-risk population having 3 or more of the following clinical characteristics: upper-body obesity, hypertriglyceridemia, low HDL, hypertension, and abnormal glucose. All of these attributes, however, are associated with increased levels of CRP. In a study, the interrelationships between CRP, the metabolic syndrome, and incident cardiovascular events was evaluated among 14,719 apparently healthy women who were followed up for an 8-year period for myocardial infarction, stroke, coronary revascularization, or cardiovascular death; 24% of the cohort had the metabolic syndrome at study entry. It was found that, at baseline, median CRP levels for those with 0, 1, 2, 3, 4, or 5 characteristics of the metabolic syndrome were 0.68, 1.09, 1.93, 3.01, 3.88, and 5.75 mg/L, respectively (Ptrend <0.0001). Over the 8-year follow-up, cardiovascular event-free survival rates based on CRP levels above or below 3.0 mg/L were similar to survival rates based on having 3 or more characteristics of the metabolic syndrome. At all levels of severity of the metabolic syndrome, however, CRP added prognostic information on subsequent risk. Additive effects for CRP were also observed for those with 4 or 5 characteristics of the metabolic syndrome. These prospective data suggest that measurement of CRP adds clinically important prognostic information to the metabolic syndrome4.
CRP and the pathogenesis of atherosclerosis: The CRP binds to lipids, especially lecithin (phosphatidyl choline), and to plasma lipoproteins, and the first suggestion of a possible relationship to atherosclerosis came when it was demonstrated that aggregated, but not native, non-aggregated, CRP selectively bound just LDL and some VLDL from whole serum. However, native CRP does bind to partially degraded, so-called modified LDL, as it is found in atheromatous plaques, and to oxidized LDL. Furthermore CRP is present in most such plaques examined ex vivo. This CRP could contribute to complement activation and thus inflammation in the plaques, and there is experimental evidence supporting a possible role of complement in atherogenesis. CRP has also been reported to stimulate tissue factor production by peripheral blood monocytes and could thereby have important pro-coagulant effects5.
Targeting CRP for the treatment of cardiovascular disease: A study, reported the design, synthesis and efficacy of 1,6-bis(phosphocholine)-hexane as a specific small-molecule inhibitor of CRP. Five molecules of palindromic compound are bound by two pentameric CRP molecules, crosslinking and occluding the ligand-binding B-face of CRP and blocking its functions. Administration of 1,6-bis(phosphocholine)-hexane to rats undergoing acute myocardial infarction abrogated the increase in infarct size and cardiac dysfunction produced by injection of human CRP. Therapeutic inhibition of CRP is thus a promising new approach to cardioprotection in acute myocardial infarction. Potential wider applications include other inflammatory, infective and tissue-damaging conditions characterized by increased CRP production, in which binding of CRP to exposed ligands in damaged cells may lead to complement-mediated exacerbation of tissue injury6.
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