Sandbox Reserved 1121: Difference between revisions

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=== CRP structure ===

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"/>

The C-reactive protein is a homopentamer of non-covalently bound subunits. Each subunit is a 25 Da protein consisting of 224 residues bound together. The secondary structure is formed of one α-helix and ~~twoantiparallel~~ β-sheets ~~(five-stranded, three-stranded and seven-stranded).~~<ref>http://www.uniprot.org/uniprot/P02741</ref> The predominant structure is β-sheet <ref>http://www.unco.edu/nhs/Chemistry/faculty/dong/pub/pentraxin.pdf</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" />

The C-reactive protein is a homopentamer of non-covalently bound subunits. Each subunit is a 25 Da protein consisting of 224 residues bound together. The secondary structure is formed of one α-helix and two antiparallel β-sheets<ref>http://www.uniprot.org/uniprot/P02741</ref>. The predominant structure is β-sheet <ref>http://www.unco.edu/nhs/Chemistry/faculty/dong/pub/pentraxin.pdf</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" />.

The diameterof 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">A. Agrawal, P. P. Singh, B. Bottazzi, C. Garlanda, A. Mantovani, Pattern recognition by Pentraxins, Adv Exp Med Biol. 2009; 653: 98-116</ref>

=== Ca2+ binding-site ===

CRP is a calcium dependent structure. Effectively, 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.<ref name="ramadan">Ramadan, M. A. M., Shrive, A. K., Holden, D., Myles, D. A. A., Volanakis, J. E., Larry J.DeLucas, L. J., Greenhough, T. J. (2002), The three-dimensional structure of calcium-depleted human C-reactive protein from perfectly twinned crystals, Acta Cryst., D58 :992-1001</ref>

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<ref name="ramadan">Ramadan, M. A. M., Shrive, A. K., Holden, D., Myles, D. A. A., Volanakis, J. E., Larry J.DeLucas, L. J., Greenhough, T. J. (2002), The three-dimensional structure of calcium-depleted human C-reactive protein from perfectly twinned crystals, Acta Cryst., D58 :992-1001</ref>.

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. <ref name="agrawal"/>

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<ref name="agrawal"/>.

=== PC binding site ===

PC stands for phosphocholine. It is a phospholipid in cell membranes and a plasma lipoproteins.<ref name="thompson">Thompson, D., Pepys, M. B., Wood, S. P. (1999), The physiological structure of human C-reactive protein and its complex with phosphocholine, Structure February 1999, 7:169–177.</ref> Phe-66 and Glu-81 are the two key residues that enable the binding of PC. <ref name="kumar"/> They interact with the choline function of PC, which therefore lies inside the PC-binding site.

PC stands for phosphocholine. It is a phospholipid in cell membranes and a plasma lipoproteins<ref name="thompson">Thompson, D., Pepys, M. B., Wood, S. P. (1999), The physiological structure of human C-reactive protein and its complex with phosphocholine, Structure February 1999, 7:169–177.</ref>. Phe-66 and Glu-81 are the two key residues that enable the binding of PC<ref name="kumar"/>. 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. <ref name="agrawal"/>

CRP can also bind chromatin, histones, small nuclear robonucleoproteins nuclear envelop proteins and nucleosomes Ca2+-dependently<ref name="agrawal"/>.

== 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. <ref name="agrawal"/> The CRP is therefore part of the acute phase response which is a rapid concentration variation of plasma proteins. <ref name = "Alex">Alexander J. Szalai, The biological functions of C-reactive protein, Vascular Pharmacology 39 (2002) 105– 107</ref>

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<ref name="agrawal"/>. The CRP is therefore part of the acute phase response which is a rapid concentration variation of plasma proteins <ref name = "Alex">Alexander J. Szalai, The biological functions of C-reactive protein, Vascular Pharmacology 39 (2002) 105– 107</ref>.

== Biomedical interest ==

Healthy humans have a CRP rate which is generally about 1 μg/mL.<ref name="kumar"/> CRP is secreted by the liver into the blood circulation. <ref name = "Alex"/> 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.<ref name="thompson" /> CRP can be defined as a target for the development of cardioprotection and neuroprotection.<ref name="kumar"/>

Healthy humans have a CRP rate which is generally about 1 μg/mL<ref name="kumar"/>. CRP is secreted by the liver into the blood circulation<ref name = "Alex"/>. 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<ref name="thompson" />. CRP can be defined as a target for the development of cardioprotection and neuroprotection<ref name="kumar"/>.

== Structural highlights ==

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@@ Line 10: / Line 10: @@
 === CRP structure ===
 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"/>
-The C-reactive protein is a homopentamer of non-covalently bound subunits. Each subunit is a 25 Da protein consisting of 224 residues bound together. The secondary structure is formed of one α-helix and twoantiparallel β-sheets (five-stranded, three-stranded and seven-stranded).<ref>http://www.uniprot.org/uniprot/P02741</ref> The predominant structure is β-sheet <ref>http://www.unco.edu/nhs/Chemistry/faculty/dong/pub/pentraxin.pdf</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" />
+The C-reactive protein is a homopentamer of non-covalently bound subunits. Each subunit is a 25 Da protein consisting of 224 residues bound together. The secondary structure is formed of one α-helix and two antiparallel β-sheets<ref>http://www.uniprot.org/uniprot/P02741</ref>. The predominant structure is β-sheet <ref>http://www.unco.edu/nhs/Chemistry/faculty/dong/pub/pentraxin.pdf</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" />.
 The diameterof 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">A. Agrawal, P. P. Singh, B. Bottazzi, C. Garlanda, A. Mantovani, Pattern recognition by Pentraxins, Adv Exp Med Biol. 2009; 653: 98-116</ref>
 === Ca<sup>2+</sup> binding-site ===
 CRP is a calcium dependent structure. Effectively, Ca<sup>2+</sup> 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 Ca<sup>2+</sup> binding too. In the absence of Ca<sup>2+</sup>, 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.<ref name="ramadan">Ramadan, M. A. M., Shrive, A. K., Holden, D., Myles, D. A. A., Volanakis, J. E.,  Larry J.DeLucas, L. J., Greenhough, T. J. (2002), The three-dimensional structure of calcium-depleted human C-reactive protein from perfectly twinned crystals, Acta Cryst., D58 :992-1001</ref>
+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<ref name="ramadan">Ramadan, M. A. M., Shrive, A. K., Holden, D., Myles, D. A. A., Volanakis, J. E.,  Larry J.DeLucas, L. J., Greenhough, T. J. (2002), The three-dimensional structure of calcium-depleted human C-reactive protein from perfectly twinned crystals, Acta Cryst., D58 :992-1001</ref>.
-The two Ca<sup>2+</sup>-binding sites are overlapping in a loop. In the absence of Ca<sup>2+</sup>, the loop changes conformaion and releases the proteolysis site. Therefore Ca<sup>2+</sup> protects CRP form proteolytic cleavage. <ref name="agrawal"/>
+The two Ca<sup>2+</sup>-binding sites are overlapping in a loop. In the absence of Ca<sup>2+</sup>, the loop changes conformaion and releases the proteolysis site. Therefore Ca<sup>2+</sup> protects CRP form proteolytic cleavage<ref name="agrawal"/>.
 === PC binding site ===
-PC stands for phosphocholine. It is a phospholipid in cell membranes and a plasma lipoproteins.<ref name="thompson">Thompson, D., Pepys, M. B., Wood, S. P. (1999), The physiological structure of human C-reactive protein and its complex with phosphocholine, Structure February 1999, 7:169–177.</ref> Phe-66 and Glu-81 are the two key residues that enable the binding of PC. <ref name="kumar"/> They interact with the choline function of PC, which therefore lies inside the PC-binding site.
+PC stands for phosphocholine. It is a phospholipid in cell membranes and a plasma lipoproteins<ref name="thompson">Thompson, D., Pepys, M. B., Wood, S. P. (1999), The physiological structure of human C-reactive protein and its complex with phosphocholine, Structure February 1999, 7:169–177.</ref>. Phe-66 and Glu-81 are the two key residues that enable the binding of PC<ref name="kumar"/>. 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 Ca<sup>2+</sup>-dependent way. The PC-binding site is next to the Ca<sup>2+</sup>-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 Ca<sup>2+</sup>. The phosphate groupe of PC interacts by coordination with the two Ca<sup>2+</sup>.
-CRP can also bind chromatin, histones, small nuclear robonucleoproteins nuclear envelop proteins and nucleosomes Ca<sup>2+</sup>-dependently. <ref name="agrawal"/>
+CRP can also bind chromatin, histones, small nuclear robonucleoproteins nuclear envelop proteins and nucleosomes Ca<sup>2+</sup>-dependently<ref name="agrawal"/>.
 == 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. <ref name="agrawal"/> The CRP is therefore part of the acute phase response which is a rapid concentration variation of plasma proteins. <ref name = "Alex">Alexander J. Szalai, The biological functions of C-reactive protein, Vascular Pharmacology 39 (2002) 105– 107</ref>
+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<ref name="agrawal"/>. The CRP is therefore part of the acute phase response which is a rapid concentration variation of plasma proteins <ref name = "Alex">Alexander J. Szalai, The biological functions of C-reactive protein, Vascular Pharmacology 39 (2002) 105– 107</ref>.
 == Biomedical interest ==
-Healthy humans have a CRP rate which is generally about 1 μg/mL.<ref name="kumar"/> CRP is secreted by the liver into the blood circulation. <ref name = "Alex"/> 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.<ref name="thompson" /> CRP can be defined as a target for the development of cardioprotection and neuroprotection.<ref name="kumar"/>
+Healthy humans have a CRP rate which is generally about 1 μg/mL<ref name="kumar"/>. CRP is secreted by the liver into the blood circulation<ref name = "Alex"/>. 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<ref name="thompson" />. CRP can be defined as a target for the development of cardioprotection and neuroprotection<ref name="kumar"/>.
 == Structural highlights ==