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Human C-reactive protein (CRP)Human C-reactive protein (CRP)
[1] [2] The C-reactive protein (CRP) is a plasma protein which belongs to the pentraxin family, mainly synthesized by the liver. Its concentration may increase rapidly, as much as 1000-fold or more, in response to tissue injury, infection and inflammation: It's an acute-phase protein.
CRP binds to phosphocholine which is exposed on died or dying cells and expressed on the surfaces of pathogens. Then, it may activate the complement system via interaction with C1q, and enhance phagocytosis by macrophages via its binding to Fcγ receptors. This suggests that CRP - in addition to the fact that this protein has been highly conserved during evolution - is a very important part of the innate immune response, in the host defense.
This feature of amount increasing of the protein is currently used as a marker of inflammation in patients.
Structure of CRPStructure of CRP
CRP is a pentamer: it contains five identical 23-kDa protomers, noncovalently associated (van der Waals contacts or hydrogen bonding) around a central pore. All members of the “pentraxins” family have this general structure.
Each protomer has a recognition face (also called face B) with a phosphocholine binding site (carrying two calcium ions), made of a two-layered β sheet. The other face - the effector face (or face A) - where complement C1q and Fc receptors bind, contains a single α helix. Consequently, the pentamer consists of five α helices on one side, and ten calcium ions on the other.
The Calcium and Phosphocholine binding sitesThe Calcium and Phosphocholine binding sites
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CalciumCalcium
[1] There are two per CRP protomer.
One is consisting of residues and the mainchain carbonyl oxygen of residue 139 of the CRP. The other contains residues of the CRP. Consequently, there are a total of five amino acids involved in the first calcium binding site, and four amino acids involved in the second site.
Contrary to SAP (serum amyloid P) – an other protein of the pentraxin family – which has respectively 6 and 3 amino acids involved in its two different calcium binding sites, both sites in CRP look like each other and have thus around the same affinity for the calcium ions. Mainly, CRP contains either no calcium bound, or the two calcium bound in its both sites.
In the first case, residues of CRP protomers – of which Asp140 and Gln150 which are a part of the calcium binding sites – form a loop far away of the body of the protein, allowing a proteolysis site previously hidden to be exposed.
In the other case, the calcium ions (separated by 4Å) are a part of the binding sites of other molecules, such as phosphocholine.
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PhosphocholinePhosphocholine
[1] Phosphocholine is an universal phospholipid found particularly in the cell membranes and plasma lipoproteins of bacteria, fungi, plants and other eukaryotic organisms whose us, the human beings. However, CRP can only bind phosphocholine of our damaged or apoptotic cells, as head groups of phosphocholine are inaccessible to CRP in “normal” cells.
Different sites of the CRP are needed to bind phosphocholine:
- A hydrophobic pocket with the two key residues located on the two extremities of the cavity. Phe66 interacts with the methyl group of the phosphocholine by hydrophobic interactions. Glu81 interacts with the positively charged choline nitrogen of the phosphocholine. The existence of this hydrophobic pocket () would allow bindings of phosphocholine analogues, maybe with higher affinity. This property is very interesting for the research of new drugs blocking the effects of CRP, sometimes harmful.
- The two bound calcium ions which interact with the phosphate group of the phosphocholine (two oxygen of the phosphate group).
The role of CRP to protect the host of infection and inflammation is thus certainly done first by binding to phosphocholine or other ligands such as phosphoethanolamine, and then by activation of the classical complement pathway via interaction with C1q or phagocytosis via interaction with Fc receptors.
Interaction with C1q and Fcγ receptorsInteraction with C1q and Fcγ receptors
C1 is the first component of the classical pathway of the complement and consists of a complex of one C1q, two C1r, and two C1s molecules. C1q is the recognition subunit whereas C1r and C1s form the catalytic subunit. C1q is composed of three different polypeptide chains A, B and C and has a total molecular mass of 460Da. Each chain is present in four copies in the C1q molecule. C1q can bind different activators such as immunoglobulin (IgM and IgG) and CRP. In red, adjacent bound CRP molecules may present multiple binding sites via the face A for the C1q arms.[3]
The bond of C1 to an activator, as CRP, triggers the activation of the classical pathway of the complement. This pathway permits, inter alia, the lysis of infectious agent. An excessive activation of the classical pathway could induce tissue injury in ischemia. Thus, the use of inhibitors that attenuate the activation of the pathway by CRP could be a therapeutic approach in ischemia injury.[4]
Various studies have shown that CRP is able to bind to Fcγ receptor with an affinity comparable to that of IgG. These receptors expressed on hematopoietic cells are able to recognize the Fc portion of IgG. They induce phagocytosis in response to immune system attack. The interaction of CRP with Fcγ receptor confirms that CRP has an important role in the immune system and could explain that CRP concentration increases during the acute phase of the inflammation.[5]
ReferencesReferences
- ↑ 1.0 1.1 1.2 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
- ↑ Black S, Kushner I, Samols D. C-reactive Protein. J Biol Chem. 2004 Nov 19;279(47):48487-90. Epub 2004 Aug 26. PMID:15337754 doi:http://dx.doi.org/10.1074/jbc.R400025200
- ↑ 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
- ↑ McGrath FD, Brouwer MC, Arlaud GJ, Daha MR, Hack CE, Roos A. Evidence that complement protein C1q interacts with C-reactive protein through its globular head region. J Immunol. 2006 Mar 1;176(5):2950-7. PMID:16493053
- ↑ Bodman-Smith KB, Gregory RE, Harrison PT, Raynes JG. FcgammaRIIa expression with FcgammaRI results in C-reactive protein- and IgG-mediated phagocytosis. J Leukoc Biol. 2004 Jun;75(6):1029-35. Epub 2004 Apr 1. PMID:15075346 doi:http://dx.doi.org/10.1189/jlb.0703306
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