Sandbox207: Difference between revisions

==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'''.[http://www.rndsystems.com/cb_detail_objectname_SU05_CReactiveProtein.aspx <1>]

===Size===

(a) Negatively stained electron micrograph showing the typical pentameric disc-like structure face-on and side-on (arrows). (b) Ribbon diagram of the crystal structure, showing the lectin fold and the two calcium atoms (spheres) in the ligand-binding site of each protomer. (c) Space-filling model of the CRP molecule, showing a single phosphocholine molecule located in the ligand-binding site of each protomer.[http://www.jci.org/articles/view/18921 <3>]]]

:Moreover, the structure of CRP is different in ill 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 a healthy 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 remain 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/ <2>]

<Structure load='1b09' size='250' frame='true' align='right' caption='CRP complexed with Phosphocholine' scene='Phosphocholine' />

:In the presence of calcium, CRP is '''specifically''' bound to <scene name='Sandbox207/Phosphocholine/9'>phosphocholine </scene> residues. We find phosphocholine in the microbial polysaccharides.

:The wide distribution of phosphocholine in polysaccharides of pathogenic and in cellular membranes allows CRP to recognize a range of pathogenic targets as well as the damaged membranes and necrosed cells of the host. The ligand, the phosphocholine, does not appear normally on the surface of cells, but '''is exposed by cellular damages caused by phospholipases'''.

:After this connection, CRP activates the '''classical complement pathway''' in the absence of antibody, and '''opsonizes ligands''', with the aim of their phagocytosis.

:Indeed, when CRP is bound to the ligand, it is recognized by the factor '''CIq''', which activates powerfully the classical complement pathway, committing the factor C3. Then there is formation of the membrane attack complex C5-C9 on the surface of the ligand, what entails its phagocytosis.

:On the recognition face, there are two binding sites of equal affinity to calcium, consisting of residues <scene name='Sandbox207/Phosphocholine/4'>Asp60, Asn61, Glu138, Asp140, and the main chain carbonyl of Gln139 -in red-</scene> for the first calcium ion and residues<scene name='Sandbox207/Phosphocholine/5'>Glu138, Asp140, Gln150, and Glu147 -in green-</scene> for the second calcium ion. An interaction appears between the two calcium ions and the oxygens of the phosphate group and the choline group, which stays in a hydrophobic pocket formed by residues <scene name='Sandbox207/Phosphocholine/7'>Phe66, Leu64, Thr76, and Glu81</scene>. The face of Phe66 (in light blue) is exposed, allowing it to have '''hydrophobic interactions''' with the methyl groups of the choline. Glu81 (in magenta) interacts with the positively charged nitrogen on choline.

7- ''C-reactive Protein at the Interface Between Innate Immunity, Inflammation: CRP Structure & Expression'', Andres Peisajovich,1 Lorraine Marnell,2 Carolyn Mold,3 Terry W Du Clos 4.

[http://www.medscape.com/viewarticle/575924_3 <7>]