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The C-reactive protein has been given this name because it precipitates the C polysaccharide in the cell wall.^[3]

Structure

CRP structure

Ser53, His95, Cys97, Asp112, Gly113, Gly136, Gly154, Val165, Leu166, Ile171, and Gly196 are the highly conserved residues in the primary sequence of CRP.^[3] The C-reactive protein is a homopentamer of non-covalently bound subunits. Each subunit is a 25 Da protein consisting of 224 residues bound together. The secondary structure is formed of one α-helix and two antiparallel β-sheets^[4]. The predominant structure is β-sheet ^[5] but short helical regions can be noticed for the residues 43 and 185.^[3] The residues Glu197 and Lys123 of CRP form an intermolecular ion pair^[6]. The diameterof the CRP pentamer is 102 Å, the inner pore diameter is 30 Å and the diameter of a subunit is 36 Å. ^[7]

Ca²⁺ binding-site

CRP is a calcium dependent structure. Effectively, Ca²⁺ is required for PC binding, and more precisely for the formation of the PC binding site thanks to structural rearrangements. The protection against denaturation and proteolysis is performed through Ca²⁺ binding too. In the absence of Ca²⁺, hCRP is cleaved between Asn145 and Phe146 by nagarse protease, and between Phe146 and Glu147 by pronase. Asp60, Asn61, Glu138, Asp140 and the main-chain carbonyl of Gln139 residues allow the first calcium ion binding, and the second is performed through Glu138, Asp140, Glu147 and Gln150^[8]. The two Ca²⁺-binding sites are overlapping in a loop. In the absence of Ca²⁺, the loop changes conformaion and releases the proteolysis site. Therefore Ca²⁺ protects CRP form proteolytic cleavage^[7].

PC binding site

PC stands for phosphocholine. It is a phospholipid in cell membranes and a plasma lipoproteins^[6]. Phe-66 and Glu-81 are the two key residues that enable the binding of PC^[3]. They interact with the choline function of PC, which therefore lies inside the PC-binding site. CRP binds the phosphocholine and other ligands in a Ca²⁺-dependent way. The PC-binding site is next to the Ca²⁺-binding sites on the same face of the CRP protein. The PC-binding site is a hydrophobic pocket constituted by the residues Leu64, Phe66, Thr76 and the two Ca²⁺. The phosphate groupe of PC interacts by coordination with the two Ca²⁺. CRP can also bind chromatin, histones, small nuclear robonucleoproteins nuclear envelop proteins and nucleosomes Ca²⁺-dependently^[7].

Function

CRP binds to PC located on the surface of bacteria that infected the organism. The resulting immune response is the phygocytosis of PC-expressing bacteria^[7]. The CRP is therefore part of the acute phase response which is a rapid concentration variation of plasma proteins ^[9].

Biomedical interest

Healthy humans have a CRP rate which is generally about 1 μg/mL^[3]. CRP is secreted by the liver into the blood circulation^[9]. CRP level is 1000 times higher in a cytokine-mediated response due to tissue injury, infection and inflammation. Therefore the CRP rate in serum is common use to detect the activity of a disease^[6]. CRP can be defined as a target for the development of cardioprotection and neuroprotection^[3].

Structural highlights

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