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=== CRP structure ===
=== CRP structure ===
Primary structure:
Primary structure:
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 <ref name="uniprot">[http://www.uniprot.org/uniprot/P02741 UniProtKB - P02741 (CRP_HUMAN)]</ref>.
The C-reactive protein is a homopentamer in which each subunit is a 25 kDa protein consisting of 224 residues <ref name="uniprot">[http://www.uniprot.org/uniprot/P02741 UniProtKB - P02741 (CRP_HUMAN)]</ref>.
Ser53, His95, Cys97, Asp112, Gly113, Gly136, Gly154, Val165, Leu166, Ile171, and Gly196 are the highly conserved residues in the primary sequence of CRP <ref name="kumar"/>.
Ser53, His95, Cys97, Asp112, Gly113, Gly136, Gly154, Val165, Leu166, Ile171, and Gly196 are the highly conserved residues in the primary sequence of CRP <ref name="kumar"/>.
Secondary structure:
Secondary structure:
The secondary structure is formed of one <scene name='71/719862/Helix/1'>α-helix</scene> and two antiparallel <scene name='71/719862/Sheet/1'>β-sheets</scene> <ref name="uniprot"/>. The predominant structure is β-sheet <ref>PMID: 1382589</ref> but short helical regions can be noticed for the residues 43 and 185 <ref name="kumar"/>. The residues Glu197 and Lys123 of CRP form an intermolecular ion pair <ref name="thompson">PMID: 10368284</ref>.
The secondary structure is formed of one <scene name='71/719862/Helix/1'>α-helix</scene> and two antiparallel <scene name='71/719862/Sheet/1'>β-sheets</scene> <ref name="uniprot"/>. The predominant structure is β-sheet <ref>PMID: 1382589</ref> but short helical regions can be noticed for the residues 43 and 185 <ref name="kumar"/>. The residues Glu197 and Lys123 of CRP form an intermolecular ion pair <ref name="thompson">PMID: 10368284</ref>.
Tertiary and quaternary structure:
Tertiary and quaternary 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 <ref name="Volanakis">PMID: 11532280</ref>.
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 and nonglycosylated that are arranged symmetrically around a central pore <ref name="Volanakis">PMID: 11532280</ref>.
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 <ref name="agrawal">PMID: 19799114 </ref>.
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 <ref name="agrawal">PMID: 19799114 </ref>.
Thereafter, the ligand-binding face of the molecule will be called B and the opposite face will be called A. The B face binds two Ca<sup>2+</sup> ions and a phosphocholine per subunit. The A face, recognizable by the presence of the α-helix, can interact with C1q and Fc receptors <ref name="duclos">PMID: 15531769 </ref>. 


=== Ca<sup>2+</sup> binding-site ===
=== Ca<sup>2+</sup> binding-site ===

Revision as of 19:37, 27 January 2016

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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 [1]. Although 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 [1].


The C-reactive protein has been given this name because it precipitates the C polysaccharide in the cell wall [2].

Structure

CRP structure

Primary structure: The C-reactive protein is a homopentamer in which each subunit is a 25 kDa protein consisting of 224 residues [3]. Ser53, His95, Cys97, Asp112, Gly113, Gly136, Gly154, Val165, Leu166, Ile171, and Gly196 are the highly conserved residues in the primary sequence of CRP [2].

Secondary structure: The secondary structure is formed of one α-helix and two antiparallel β-sheets [3]. The predominant structure is β-sheet [4] but short helical regions can be noticed for the residues 43 and 185 [2]. The residues Glu197 and Lys123 of CRP form an intermolecular ion pair [5].

Tertiary and quaternary 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 and nonglycosylated that are arranged symmetrically around a central pore [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]. Thereafter, the ligand-binding face of the molecule will be called B and the opposite face will be called A. The B face binds two Ca2+ ions and a phosphocholine per subunit. The A face, recognizable by the presence of the α-helix, can interact with C1q and Fc receptors [8].

Ca2+ binding-site

CRP is a calcium dependent structure. In fact, 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 [9]. 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 [5]. Phe-66 and Glu-81 are the two key residues that enable the binding of PC [2]. 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].

Phosphocholine-binding site [10]

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 [11].

Biomedical interest

Healthy humans have a CRP rate which is generally about 1 μg/mL[2]. CRP is secreted by the liver into the blood circulation[11]. 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[5]. CRP can be defined as a target for the development of cardioprotection and neuroprotection[2].

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.

</StructureSection>

References

  1. ↑ 1.0 1.1 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
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Kumar SV, Ravunny RK, Chakraborty C. Conserved domains, conserved residues, and surface cavities of C-reactive protein (CRP). Appl Biochem Biotechnol. 2011 Sep;165(2):497-505. doi: 10.1007/s12010-011-9270-7., Epub 2011 May 4. PMID:21541851 doi:https://dx.doi.org/10.1007/s12010-011-9270-7
  3. ↑ 3.0 3.1 UniProtKB - P02741 (CRP_HUMAN)
  4. ↑ 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
  5. ↑ 5.0 5.1 5.2 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
  6. ↑ Volanakis JE. Human C-reactive protein: expression, structure, and function. Mol Immunol. 2001 Aug;38(2-3):189-97. PMID:11532280
  7. ↑ 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
  8. ↑ Du Clos TW, Mold C. C-reactive protein: an activator of innate immunity and a modulator of adaptive immunity. Immunol Res. 2004;30(3):261-77. PMID:15531769 doi:https://dx.doi.org/10.1385/IR:30:3:261
  9. ↑ 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
  10. ↑ The PyMOL Molecular Graphics System, Version 1.8 Schrödinger, LLC.
  11. ↑ 11.0 11.1 Szalai AJ. The biological functions of C-reactive protein. Vascul Pharmacol. 2002 Aug;39(3):105-7. PMID:12616974
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