Sandbox Reserved 830

This Sandbox is Reserved from 06/12/2018, through 30/06/2019 for use in the course "Structural Biology" taught by Bruno Kieffer at the University of Strasbourg, ESBS. This reservation includes Sandbox Reserved 1480 through Sandbox Reserved 1543.

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Oncostatin M, also called OSM, is encoded by the OSM gene and is mostly produced in the end of the activation of macrophages and T cells. OSM belongs to the family of gp130 cytokines implying that it signals through the receptors containing gp130. OSM has been shown to have a lot of pleiotropic functions in cell proliferation, differentiation and inflammatory response. Thus, studies highlight its roles in cancer, bone and liver metabolism alteration, as well as in severe inflammatory diseases, such as lung and skin inflammatory diseases, atherosclerosis, cardiovascular diseases, and rheumatoid polyarthritis.

spinqualitylabelsall models PDB ID 1evs Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image
1evs, resolution 2.20Å ()
Structural annotation: Resources: CATH : 1Evsa00 InterPro : Ipr012351, Ipr001581, Ipr009079, Ipr003623 Pfam : PF01291 SCOP : d1evsa_ UniProt : P13725
Functional annotation: Cellular component: extracellular space extracellular region Biological process: tyrosine phosphorylation of Stat1 protein response to heat apoptosis multicellular organismal development negative regulation of cell proliferation cell proliferation immune response tyrosine phosphorylation of Stat3 protein peripheral nervous system development negative regulation of hormone secretion tyrosine phosphorylation of Stat5 protein cell-cell signaling behavioral response to pain regulation of cell growth Molecular function: oncostatin-M receptor binding cytokine activity
Resources:	FirstGlance, OCA, RCSB, PDBsum
Coordinates:	save as pdb, mmCIF, xml

StructureStructure

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 structure (Fig.1).

Fig.1 Ribbon colored diagram of hOSM from N-terminus in blue to the C-terminus in red. The two disulphide bonds are shown as ball-and-sticks models with the sulphur atoms represented as yellow spheres. The CD loop as observed in LIF is represented by the transparent dotted section.

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 .

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 () induced by a disruption in the helical conformation, due to the Gln25 and Leu30 hydrogen bonds with four water molecules. 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 , Phe56, Tyr173, Phe169 and Phe176 on one hand, and Phe170, Phe185 and Trp187 on the other hand. All these aromatic residues belong to helix D, , highlighting the hydrophobicity of helix D.

connects the N-terminal loop (Gly4-Glu9) preceding helix A to the C terminus of helix C. links the start of the AB loop to the N-Terminal region of helix D.

The AB loop is composed of , 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 .

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 which are situated in helix C. Two other residues contribute to the linking: , located in helix A. OSMR allows binding of OSM on three residues: Tyr196, Phe169 and Glu282. Site 3 of OSM binds to LIFR or OSMR thanks to two residues: , located in the N-terminal end of helix D. These amino acids are conserved in all cytokines.

FunctionsFunctions

Oncosatin M binds to two different receptors which are heterodimers: gp130/LIFRα and OSMRβ/gp130. These receptors are present on a lot of different cell lines. Binding of OSM on its receptors activates several signaling pathways like JAK/STAT3, MAP Kinase (MAPK), and PI3′Kinase (PI3′K). The chosen pathway depends on the cell type.

Fig.2 The different pathways in which oncostatin M is involved.

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 grants an invasive phenotype to 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.

DiseaseDisease

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.

Defects in OSM and OSMR impact metastatic melanoma cell lines due to the PKC Δ-dependent phosphorylation of Ser727 on STAT-3 and other signaling pathways. Moreover some epigenetic mechanisms have been shown to be responsible for altering the nature of metastatic melanoma, increasing OSMR expression and responsiveness of the cells.

Defects in OSM induce high levels of osteoblasts and osteoblast markers in differentiated osteosarcoma cells dramatically enhancing the proliferation of osteosarcoma cells, while stimulating an invasive phenotypic alteration of these cells mainly by the MMP-2 and VEGF expression, mediated by STAT-3.

OSM has been shown to stimulate the proliferation of Ewing sarcoma cell lines, 22Rv1 prostate cancer cells, SKOV3 ovarian cancer cells, while an increase in OSMR expression has been found in cervical carcinoma.

OSMR modifications were found to enhance human lung carcinoma development by reducing the cells’ sensitivity to OSM.

Epigenetic mutations, such as methylation, cause the silencing of OSMR, thus the inhibition of both colon cancer cell lines and papillary thyroid cancer cell proliferation.

ReferencesReferences

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ContributorsContributors

Tristan Butaye and Vincent Saravaki