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Sandbox Reserved 1134

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This Sandbox is Reserved from 15/12/2015, through 15/06/2016 for use in the course "Structural Biology" taught by Bruno Kieffer at the University of Strasbourg, ESBS. This reservation includes Sandbox Reserved 1120 through Sandbox Reserved 1159.

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1 Function and Structure
2 Action principle
3 Ligands
4 Evolutionary Conservation
5 Diseases
6 Structural highlights
7 Synthesis

Function and Structure

Human synthetic monocyte chemoattractant protein 1 (MCP) belongs to the superfamily of chemokines, which are proteins involved in immunoregulatory and inflammatory processes. On chromosome 17 in region 17q11.2-q12 is the gene MCP1. The superfamily can be subdivided into 4 smaller groups, depending on the N-ter arangment of the cysteines. The MCP1^[1] is also known as chemokine (C-C motif) ligand or:
- CCL2
- small inducible cytokine A2 (SCYA2)
- MCAF
- GDCF-2
- SMC-CF
- HSMCR30
- MGC9434
- GDCF-2
- HC11

It exists as a monomer or a dimer, even though the homodimer form is preferred.

The structure of the monomer is made of .

Action principle

MCP1 is secreted thanks to variety of cells including endothelial cells, fibroblasts, epithelial, and smooth muscle. It acts by attracting some of the immune cells like monocytes and lymphocytes. These cells are equipped with a CCR2 receptor coupled with a G protein that can recuits MCP1. MCP1 apply its chemotaxis power thanks to a concentration gradient : immune cells move from region with low concentration of MCP1 to region where a lot of MCP1 is secreted. Monocytes will then themselves be matured in macrophages that are able to secrete MCP1 in order to recruit more immune cells on the damage tissue.

Ligands

To see the ligands it binds to, please show the and then show the binding sites for and ions. The PO4 binds to the K35, S33 and S34 of the monomer and K binds to F15, N14 and N17.

Evolutionary Conservation

Check, as determined by ConSurfDB.

Diseases

MCP1 is implicated in several diseases like psoriasis and rheumatoid arthritis where the appear to recruit macrophages, therefore bolstering the inflammation on joints. It is thought to be involved in atherosclerosis in the recruitment of monocytes into the arterial wall as well as in prostate cancer^[2]. It has also been found elevated in the urine of people with lupus as a sign warning of inflammation of the kidney. MCP1 is overexpressed in epilepsy, brain ischemia, Alzheimer's disease, EAE and traumatic brain injury.

Structural highlights

MCP1 is part of the C-C motif group because of the covalent bond made between .^[3] Post translational modifications at the N-terminus can regulate receptor and target cell selectivity. Deletion of the N-terminal residue converts it from an activator of basophil to an eosinophil chemoattractant.

Synthesis

Thanks to a combination of solid phase peptide synthesis (SPPS) and native chemical ligation (NCL), MCP1 was synthesized. Its thioester-peptide segment was made by using the sulfonamide safety-catch linker and 9-fluorenylmethoxycarbonyl (Fmoc) SPPS and that is probably one of the first crystal structures prepared using these techniques. To facilitate the synthesis of both MCP1 fragments, pseudoproline dipeptides were used. Then, NCL was used to assembly the all chain and MCP1 was folded and oxidized by a glutathione redox buffer. MCP1 was crystallized and the structure was determined by X-ray diffraction at 1.9-A resolution.

References

https://fr.wikipedia.org/wiki/CCL2 http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1DOK http://www.uniprot.org/uniprot/P13500#interaction http://www.rcsb.org/pdb/explore/explore.do?structureId=3IFD

↑ Carr MW, Roth SJ, Luther E, Rose SS, Springer TA. Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3652-6. PMID:8170963
↑ Ito Y, Ishiguro H, Kobayashi N, Hasumi H, Watanabe M, Yao M, Uemura H. Adipocyte-derived monocyte chemotactic protein-1 (MCP-1) promotes prostate cancer progression through the induction of MMP-2 activity. Prostate. 2015 Jul 1;75(10):1009-19. doi: 10.1002/pros.22972. Epub 2015 Apr 27. PMID:25917126 doi:http://dx.doi.org/10.1002/pros.22972
↑ Lubkowski J, Bujacz G, Boque L, Domaille PJ, Handel TM, Wlodawer A. The structure of MCP-1 in two crystal forms provides a rare example of variable quaternary interactions. Nat Struct Biol. 1997 Jan;4(1):64-9. PMID:8989326

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Sandbox Reserved 1134

From Proteopedia

Contents

Function and Structure

Action principle

Ligands

Evolutionary Conservation

Diseases

Structural highlights

Synthesis

References

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