Sandbox207

From Proteopedia

Revision as of 13:38, 29 December 2011

This page is reserved for a work from two students in ESBS (A.Butet and E.Rosati) Thanks.

spinqualitylabelsall models PDB ID 1gnh Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image
1gnh, resolution 3.00Å ()
Ligands:
Structural annotation: Resources: CATH : 1Gnha00, 1Gnhb00, 1Gnhc00, 1Gnhd00, 1Gnhe00, 1Gnhf00, 1Gnhg00, 1Gnhh00, 1Gnhi00, 1Gnhj00 InterPro : Ipr001759, Ipr013320, Ipr008985 Pfam : PF00354 SCOP : d1gnha_, d1gnhb_, d1gnhc_, d1gnhd_, d1gnhe_, d1gnhf_, d1gnhg_, d1gnhh_, d1gnhi_, d1gnhj_ UniProt : P02741
Functional annotation: Cellular component: extracellular region Biological process: inflammatory response acute-phase response Molecular function: binding calcium ion binding metal ion binding
Evolutionary conservation: Toggle Conservation Colors: Further Information: Caveats, Explanation, Complete Results at ConSurfDB
Resources:	FirstGlance, OCA, RCSB, PDBsum
Coordinates:	save as pdb, mmCIF, xml

C-reactive protein, CRP

Structure

Gene structure, family

The CRP gene is located on chromosome 1q23. It is composed of two exons and one intron. This gene is regulated by interleukin-6, the principal inducer of the gene during the acute phase. CRP is secreted by hepatocytes.

The Human CRP belongs to the pentraxin family of proteins having five identical, non-covalently associated subunits that form a symmetrical homopentameric ring. The pentraxin family is highly conserved in evolution.

Size

Each subunit contains 206 amino acid residues (approximately 23kDa) and is non-glycosylated. The outside diameter of the pentamer is 102 Å, the diameter of the inner core is 30 Å, and the diameter of the protomer is 36 Å.

Detailed strucutre

Each promoter consists of two anti-parallel β sheets (the lectin fold) with an α helix on the effector face of the protein. The ligand biding site is located on the concave face of the protein, and is composed of loops with 2 calcium ions bound 4 Å apart by protein side-chains.

The recognition face contains the which consists of two coordinated calcium ions next to a hydrophobic pocket in which the phosphocholine stays.

There are interpromoter interactions between the subunits: three salt bridges are included and the 115-123 loop of one protomer and the 40-42 and 197-202 regions of adjacent protomers are involved. Moreover, the subunits are capable to rotate by 15-20° around an axis parallel to the central alpha-helix.

Thanks to this rotation, the alpha-helices can lie closer to the axis of the pentamere, therefore bringin the bound Ca2+ further away from it. On each subunit, we can find phosphocholine bound in a shallow surface pocket. With the help of phosphate groups and Glu81 via the choline moiety, the phosphocholine can interact with the two protein-bound ions.

Moreover, the structure of CRP is different in diseased patients. Indeed, in some pathological conditions, the Human CRP is glycosylated. Analysis of the structure showed the systematic absence of two peptide fragments, one at the N-terminus (loop 1-6) in all patients, the other near the C-terminus (loop 189-191) in patients with osteogenic sarcoma and Cushing's syndrome. In an undiseased individual, glycosylation sites are inacessible due to the presence of the N-terminal. The loss of these two fragments exposed two potential glycosylation sites on a cleft door. The functional areas of the pentraxin structure remains the same since the Ca2+ and phosphocholine sites are on the opposite site of the pentraxin molecule.

http://biology.kenyon.edu/BMB/Chime2/2005/Jenny/FRAMES/

Marqueur biologique

The CRP concentration is a very useful nonspecific biochemical marker of inflammation and/or tissue damage. It is used since 1977 in the diagnosis and the supervision of the evolution of the infections, because the normalization of its rate is an indication that the infectious phenomenon is mastered. The C Reactive Protein is also a predictive biomarker for cardiovascular disease risk.

In healthy young adult, the median concentration of CRP is 0.8 mg/l. This value may increase from less than 50 μg/l to more than 500 mg/l (10,000-fold), following an acute-phase stimulus. After a single stimulus, serum concentration of CRP is rising above 5 mg/l by about 6 hours. This increase is proportional to the intensity of the inflammation. The peak is reached around 48 hours. When the stimulus ceases, the circulating CRP concentration falls rapidly.

It exists individual variability in baseline CRP, whether resulting from non-genetic or genetic factors. Indeed, a polymorphism in the CRP gene intron and promoter has been described, that cause perturbations to normal expression levels.

The intron of the gene of the CRP is formed by 278 nucleotides, containing a segment of 39 nucleotides rich in GT bases. This segment could be responsible for the training of the left-handed helix of the Z-form DNA of the CRP. The individuals possessing a particular allele combination have a lower concentration of the CRP. It is probably due to structural modifications of the DNA which would affect the transcription of the gene.

Within the promoter, several polymorphisms were discovered in transcription factor binding E-box sites, what would significantly seem to influence the rate of the CRP into the blood.

This variability should be accounted for when using the CRP as a predictive biomarker.