Sandbox Reserved 830: Difference between revisions

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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.

[[Image:Oncostatin structure.png|frame|left|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|~~right~~|Stereodiagram of the Cα trace for hOSM.]]

[[Image:Oncostatin structure.png|frame|left|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.

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.

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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.

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<ref name="first">PMID: 10997905</ref>.

[[Image:Osm interact osmr.png|frame|left|Complimentarity between the interaction surfaces of hOSM and gp130.The solvent-accessible surfaces of site 2 on hOSM (left) and the cognate binding site on gp130 (right) are displayed with areas contributed by residues implicated in binding highlighted as coloured patches. The orientation for hOSM site 2 is rotated 90° from that in Figure 4 whereas gp130 is rotated by 180° from its orientation relative to hOSM in the putative interaction complex, as in the opening of a book. Residues not implicated in gp130 binding are in light-blue, those with some effect are yellow, residues critical for gp130 binding are green and those critical for LIFR binding are red.]] [[Image:Oncostatin site3.jpg|frame|center]]

[[Image:Osm interact osmr.png|frame|left]] [[Image:Oncostatin site3.jpg|frame|center]]

==Functions==

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.

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<ref name="second">PMID: 24381786</ref>.

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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<ref name="third">PMID: 10446061</ref>. 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<ref name="second">PMID: 24381786</ref>. Physiological function of OSM in the central nervous system remains unknown<ref name="fourth">PMID: 14985435</ref>.

==Disease==

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@@ Line 12: / Line 12: @@
 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|left|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|right|Stereodiagram of the Cα trace for hOSM.]]
+[[Image:Oncostatin structure.png|frame|left|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.
 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.
@@ Line 27: / Line 24: @@
 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.
+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<ref name="first">PMID: 10997905</ref>.
-[[Image:Osm interact osmr.png|frame|left|Complimentarity between the interaction surfaces of hOSM and gp130.The solvent-accessible surfaces of site 2 on hOSM (left) and the cognate binding site on gp130 (right) are displayed with areas contributed by residues implicated in binding highlighted as coloured patches. The orientation for hOSM site 2 is rotated 90° from that in Figure 4 whereas gp130 is rotated by 180° from its orientation relative to hOSM in the putative interaction complex, as in the opening of a book. Residues not implicated in gp130 binding are in light-blue, those with some effect are yellow, residues critical for gp130 binding are green and those critical for LIFR binding are red.]] [[Image:Oncostatin site3.jpg|frame|center]]
+[[Image:Osm interact osmr.png|frame|left]] [[Image:Oncostatin site3.jpg|frame|center]]
 ==Functions==
 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.
+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<ref name="second">PMID: 24381786</ref>.
@@ Line 45: / Line 39: @@
-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<ref name="third">PMID: 10446061</ref>. 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<ref name="second">PMID: 24381786</ref>. Physiological function of OSM in the central nervous system remains unknown<ref name="fourth">PMID: 14985435</ref>.
 ==Disease==