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C-Reactive Protein (CRP) is considered to be a normal plasma protein such that its concentration rises as a cytokine-mediated response resulting from tissue injury, infection or inflammation [1]. It's unique structure puts it in the pentraxin family which includes serum amyloid P component (SAP) and it consists of five identical, non-covalently associated protomers that are arranged in a symmetrical fashion weighing ~ 23kDa [1]. Since it's structure is highly conserved, the calcium dependent binding site allows found within CRP allows for strong binding to phosphocholine (PC) along with other structures and this makes it physiologically relevant. Some recent studies have made a prognostic comparison with increased CRP levels and coronary heart disease, thus reinforcing the idea that CRP also plays a significant role as a future therapeutic target [1].

Structure and Function

CRPs five promoter structures are folded into two anti-parallel β-sheets with flattened jellyroll topologies. Each promoter contains a recognition face with a phosphocholine binding site consisting of two coordinated calcium ions adjacent to a hydrophobic pocket. The co-crystallized structure of CRP with phosphocholine suggest that Phe-66 and Glu-81 are two key residues that mediate binding between phosphocholine and CRP. More specifically, Phe-66 provides hydrophobic interactions with the methyl groups of phosphocholine. Similarly, Glu-81 is found on the opposite end of the pocket where it interacts well with the positively charged choline nitrogen. Present on the opposite face of the pentamer is the effector face, where the presumed C1q and Fcγ receptors bind

Typically, after After an acute inflammatory stimulus, CRP is synthesized by hepatocytes. CRP sits on the short arm of chromosome 1 (in humans) and it contains only one intron and it is regulated at the transcriptional level by cytokine interleukin-6 (IL-6) and by interleukin-1β (IL-1β). Both IL-6 and IL-1β control expression of many acute phase protein genes through activation of several transcription factors including STAT3, C/EBP family members and Rel proteins (NF-κB).

Some of the biological effects/functions of CRP include: CRP's unique ability to only bind to phosphocholine ligands of either damaged or apoptotic cells. Additionally, CRP can bind to other ligands such as phosphoethanolamine, chromatin, histones, fibronectin, small nuclear ribonucleoproteins, laminin, and polycations. CRP also contains pleiotropic effects which produce both pro and anti-inflammatory responses.

Structure of CRP promoter

Based on homology modeling, CRP structure was found to be similar to that of SAP. The subunits within the structure consisted of a two-layered β sheet with a flattened jelly roll topology. Additionally, there is a presence of two calcium ions that are bound 4 Å apart by protein sidechains, and this is the site of ligand binding, which is referred to as the B side. The other side, designated A hosts a single α, and the pentameric disc shows five helices on one side with ten calcuim ions on the other. The side walls on the A face are constructed from Ser5, Arg6, Gln203, Pro206, Trp187, Arg188, Asn160, Gly177, Leu176, Try175, His95 and Asp112. The bottom side of CRP consiss of ASn158, His38, Leu37, Val94 and Asp112.

Biological Implications

It is known that CRP belongs to a highly conserved pentraxin class that is responsible for innate immunity and it aids in the prevention of developing an autoimmunity ^[1] COmplexed or aggregated CRP activates complent, with pro-inflammatory effects. For instance, a direct correlation has been made between increased levels of CRP to complications of atherosslerosis which may include a mycardial infarction. In addition, CRP has the ability to predict future outcomes as a result of the infarction. Furthermore, it was discovered that CRP actually

Structure of CRP pentamer

In CRP, each subunit in CRP is rotated by 22° towards the five-fold axis in comparison to SAP, where the subunits are planar to each other.Also,

Comparison of human CRP to other pentraxins

When the CRP structure is complexed with PC, major interactions that occur between two phosphate oxygens and the calciums and between the positively charged quaternary nitrogen of PC and the negatively charged sidechain of Glu81. Also, another difference is the ability f

CRP Role in Atherosclerosis

Human Recombinant CRP has been determined to serve as a mediator of atherosclerosis. CRP has been shown to initiate IL-6 and endothelin-1 release from endothelial cells

References

1. ↑ author,title