Sandbox Reserved 830: Difference between revisions

OSM is a compact molecule with dimensions of approximately 20 Å x 27 Å x 56 Å, that fit with the up-up-down-down four-helix bundle structure.

OSM structure is composed of the four main  α helical region (helix A, residues 10–37; helix B, residues 67–90; helix C, residues 105–131; helix  D, residues 159–185) linked by two long overhand loops (AB loop, residues 38–66; CD loop, residues 130–158) and one short loop (BC loop, residues 91–104). Globally, OSM arrangement corresponds to A-D forming one pair of helices which is parallel to the B-C pair.  

Helices A and C have breaks in the hydrogen-bonding pattern of their structure, forming tight substitute hydrogen bonds with water molecules. Indeed, it results in a kink in helix A (and slightly in helix C between residues Gln112 and Pro116) induced by a disruption in the helical conformation, due to the Gln25 and Leu30 hydrogen bonds with four water molecules. Helix A residues between Thr27 and Ile37 take on a 310 helix conformation. With this curved structure, helices A and C enhance the compaction of the A-D and B-C parallel helix pairs, causing the core of OSM to be isolated from the solvent.  

This core is composed of two aromatic stacking groups, Phe56, Tyr, 173, Phe169 and Phe176 on one hand, and Phe170, Phe185 and Trp187 on the other hand. All these aromatic residues belong to helix D, except Phe56 (AB loop) and Phe70 (Helix B), highlighting the hydrophobicity of helix D.  

The disulphide bridge between Cys6 and Cys127 connects the N-terminal loop (Gly4-Glu9) preceding helix A to the C terminus of helix C. The second disulphide bridge between Cys49 and 167 links the start of the AB loop to the N-Terminal region of helix D.  

The AB loop is composed of two α-helices from Pro43 to Arg46 and Glu59 to Gly64, while the residues in between pack closely and extensively against helix D. Comparatively, BC and CD loops are less stacking to the core. The BC loop located on the top of the four-helix bundle exhibits an important amount of B factors, along with several more classical secondary structures, which are a 310 helix between residues Ala95 and Asp97 followed by the α helix up to Ser101.  

OSM contains two binding sites for the heterodimer receptor: site 2 and site 3.

Site 2 of OSM binds to gp130 subunit with four residues located in helices A and C. The most important residues are Asn124 and Gly120 which are situated in helix C. Two other residues contribute to binding the linking: Gln16 and Gln20, located in helix A. OSMR allows binding of OSM on three residues: Tyr196, Phe169 and Glu282.

Activation of those pathways stimulates several responses. The main one is proliferation of a lot of different cell lines by increasing production of molecules, such as proliferation factors and metalloproteinase inhibitors.  In endothelial cells, vascular endothelial growth factors (VEGF) are secreted, promoting angiogenesis. Binding of OSM induces inhibition of other cell proliferation, like stem cells or tumor cells, by blocking the cell cycle in G2/M. Binding of OSM grant an invasive phenotype of cells by stimulation of chemokine secretion (like eotaxin). Chemokine allows activation of immune cells as well, and then stimulates the production of antibodies. Physiological function of OSM in the central nervous system remains unknown.

==Disease==

Oncostatin M is a pleiotropic protein and it takes part in the regulation of several organ systems. Thus, OSM is involved in a lot of pathologies mainly due to its large signaling functions targeting so many different cell types. OSM impacts cell proliferation and stimulate angiogenesis, thus its alterations greatly increase the risks of tumor growth and cancer development.