Sandbox Reserved 1121

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This Sandbox is Reserved from 15/12/2015, through 15/06/2016 for use in the course "Structural Biology" taught by Bruno Kieffer at the University of Strasbourg, ESBS. This reservation includes Sandbox Reserved 1120 through Sandbox Reserved 1159.

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Human C-reactive protein complexed with phosphocholine

Human C-Reactive Protein (CRP) is an acute phase protein belonging to the highly conserved pentraxin protein family . Althought it is a normal serum protein, its circulating concentration raises rapidly and extensively in a cytokine-mediated in response to an infection, an inflammation or a tissue injury. In this way, serum CRP rate is empirically dose to detect many human disease .

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

Structure

CRP structure

The structure of CRP has been determined by X-ray crystallograph at 3 Å resolution. Like SAP, the protein consists of five protomers, uncovalently bonded, arranged symmetrically around a central pore .

Ser53, His95, Cys97, Asp112, Gly113, Gly136, Gly154, Val165, Leu166, Ile171, and Gly196 are the highly conserved residues in the primary sequence of CRP .

The C-reactive protein is a homopentamer of non-covalently bound subunits. Each subunit is a 25 kDa protein consisting of 224 residues bound together. The secondary structure is formed of one α-helix and two antiparallel β-sheets . The predominant structure is β-sheet but short helical regions can be noticed for the residues 43 and 185 . The residues Glu197 and Lys123 of CRP form an intermolecular ion pair . The diameter of the CRP pentamer is 102 Å, the inner pore diameter is 30 Å and the diameter of a subunit is 36 Å .

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 . 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 .

PC binding site

PC stands for phosphocholine. It is a phospholipid in cell membranes and a plasma lipoproteins . Phe-66 and Glu-81 are the two key residues that enable the binding of PC . 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 .

Phosphocholine-binding site

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 . The CRP is therefore part of the acute phase response which is a rapid concentration variation of plasma proteins .

Biomedical interest

Healthy humans have a CRP rate which is generally about 1 μg/mL. CRP is secreted by the liver into the blood circulation. 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. CRP can be defined as a target for the development of cardioprotection and neuroprotection.

Structural highlights

This is a sample scene created with SAT to color by Group, and another to make a transparent representation of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

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