C-reactive protein (CRP) is an evolutionarily conserved protein. From arthropods to humans, CRP has been found in every organism where the presence of CRP has been sought. Human CRP is a pentamer made up of five identical subunits which binds to phosphocholine (PCh) in a Ca 2+ -dependent manner. In various species, we define a protein as CRP if it has any two of the following three characteristics: First, it is a cyclic oligomer of almost identical subunits of molecular weight 20–30 kDa. Second, it binds to PCh in a Ca 2+ -dependent manner. Third, it exhibits immunological cross-reactivity with human CRP. In the arthropod horseshoe crab, CRP is a constitutively expressed protein, while in humans, CRP is an acute phase plasma protein and a component of the acute phase response. As the nature of CRP gene expression evolved from a constitutively expressed protein in arthropods to an acute phase protein in humans, the definition of CRP became distinctive. In humans, CRP can be distinguished from other homologous proteins such as serum amyloid P, but this is not the case for most other vertebrates and invertebrates. Literature indicates that the binding ability of CRP to PCh is less relevant than its binding to other ligands. Human CRP displays structure-based ligand-binding specificities, but it is not known if that is true for invertebrate CRP. During evolution, changes in the intrachain disulfide and interchain disulfide bonds and changes in the glycosylation status of CRP may be responsible for different structure-function relationships of CRP in various species. More studies of invertebrate CRP are needed to understand the reasons behind such evolution of CRP. Also, CRP evolved as a component of and along with the development of the immune system. It is important to understand the biology of ancient CRP molecules because the knowledge could be useful for immunodeficient individuals.

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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The aim of this study was to test the hypothesis that C-reactive protein (CRP) protects against the development of atherosclerosis and that a conformational alteration of wild-type CRP is necessary for CRP to do so. Atherosclerosis is an inflammatory cardiovascular disease and CRP is a plasma protein produced by the liver in inflammatory states. The co-localization of CRP and low-density lipoproteins (LDL) at atherosclerotic lesions suggests a possible role of CRP in atherosclerosis. CRP binds to phosphocholine-containing molecules but does not interact with LDL unless the phosphocholine groups in LDL are exposed. However, CRP can bind to LDL, without the exposure of phosphocholine groups, if the native conformation of CRP is altered. Previously, we reported a CRP mutant, F66A/T76Y/E81A, generated by site-directed mutagenesis, that did not bind to phosphocholine. Unexpectedly, this mutant CRP, without any more conformational alteration, was found to bind to atherogenic LDL. We hypothesized that this CRP mutant, unlike wild-type CRP, could be anti-atherosclerotic and, accordingly, the effects of mutant CRP on atherosclerosis in atherosclerosis-prone LDL receptor-deficient mice were evaluated. Administration of mutant CRP into mice every other day for a few weeks slowed the progression of atherosclerosis. The size of atherosclerotic lesions in the aorta of mice treated with mutant CRP for 9 weeks was ∼40% smaller than the lesions in the aorta of untreated mice. Thus, mutant CRP conferred protection against atherosclerosis, providing a proof of concept that a local inflammation-induced structural change in wild-type CRP is a prerequisite for CRP to control the development of atherosclerosis.

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