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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 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. | ||
[[Image:Oncostatin structure.png|frame| | [[Image:Oncostatin structure.png|frame|right|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.]] [[Image:Oncostatin structure2.png|frame|center|Stereodiagram of the Cα trace for hOSM.]] | ||
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. | 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. | 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. | 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 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. | 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. | 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. | 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. | ||
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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. | 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== | ==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. | 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. | ||
Revision as of 12:11, 9 January 2014
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| 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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HUMAN ONCOSTATIN MHUMAN ONCOSTATIN M
IntroductionIntroduction
Oncostatin M is encoded by the OSM gene and it 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 disease, such as lung and skin inflammatory disease, atherosclerosis, cardiovascular diseases, and rheumatoid polyarthritis.
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 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. Site 3 of OSM binds to LIFR or OSMR thanks to two residues: Phe160 and Lys163, 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.
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.
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 Ser 727 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 OMS 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 STAT3. 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.