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Human C-reactive protein complexed with phosphocholine
This is a default text for your page '. Click above on edit this page' to modify. Be careful with the < and > signs. You may include any references to papers as in: the use of JSmol in Proteopedia [1] or to the article describing Jmol [2] to the rescue.
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 diameter of 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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References
- ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:https://dx.doi.org/10.1002/ijch.201300024
- ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Kumar, S. V., Ravunny, R. K., Chakraborty, C. (2011), Conserved Domains, Conserved Residues, and Surface Cavities of C-reactive Protein (CRP), Appl Biochem Biotechnol, 165:497–505
- ↑ UniProtKB - P02741 (CRP_HUMAN)
- ↑ Dong A, Caughey B, Caughey WS, Bhat KS, Coe JE. Secondary structure of the pentraxin female protein in water determined by infrared spectroscopy: effects of calcium and phosphorylcholine. Biochemistry. 1992 Oct 6;31(39):9364-70. PMID:1382589
- ↑ 6.0 6.1 6.2 Thompson D, Pepys MB, Wood SP. The physiological structure of human C-reactive protein and its complex with phosphocholine. Structure. 1999 Feb 15;7(2):169-77. PMID:10368284
- ↑ 7.0 7.1 7.2 7.3 Agrawal A, Singh PP, Bottazzi B, Garlanda C, Mantovani A. Pattern recognition by pentraxins. Adv Exp Med Biol. 2009;653:98-116. PMID:19799114
- ↑ Ramadan MA, Shrive AK, Holden D, Myles DA, Volanakis JE, DeLucas LJ, Greenhough TJ. The three-dimensional structure of calcium-depleted human C-reactive protein from perfectly twinned crystals. Acta Crystallogr D Biol Crystallogr. 2002 Jun;58(Pt 6 Pt 2):992-1001. Epub, 2002 May 29. PMID:12037301
- ↑ 9.0 9.1 Alexander J. Szalai, The biological functions of C-reactive protein, Vascular Pharmacology 39 (2002) 105– 107
