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| | ==Crystal Structure of RON Sema-PSI-IPT1 extracellular domains in complex with MSP beta-chain== | | ==Crystal Structure of RON Sema-PSI-IPT1 extracellular domains in complex with MSP beta-chain== |
| - | <StructureSection load='4qt8' size='340' side='right' caption='[[4qt8]], [[Resolution|resolution]] 3.00Å' scene=''> | + | <StructureSection load='4qt8' size='340' side='right'caption='[[4qt8]], [[Resolution|resolution]] 3.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4qt8]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QT8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4QT8 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4qt8]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QT8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QT8 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4fww|4fww]], [[2asu|2asu]]</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4qt8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qt8 OCA], [https://pdbe.org/4qt8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qt8 RCSB], [https://www.ebi.ac.uk/pdbsum/4qt8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qt8 ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MST1R, PTK8, RON ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), D3F15S2, DNF15S2, HGFL, MSI1, MST1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4qt8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qt8 OCA], [http://pdbe.org/4qt8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4qt8 RCSB], [http://www.ebi.ac.uk/pdbsum/4qt8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4qt8 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/RON_HUMAN RON_HUMAN]] Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to MST1 ligand. Regulates many physiological processes including cell survival, migration and differentiation. Ligand binding at the cell surface induces autophosphorylation of RON on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1 or the adapter GAB1. Recruitment of these downstream effectors by RON leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. RON signaling activates the wound healing response by promoting epithelial cell migration, proliferation as well as survival at the wound site. Plays also a role in the innate immune response by regulating the migration and phagocytic activity of macrophages. Alternatively, RON can also promote signals such as cell migration and proliferation in response to growth factors other than MST1 ligand.<ref>PMID:7939629</ref> <ref>PMID:9764835</ref> <ref>PMID:18836480</ref> | + | [https://www.uniprot.org/uniprot/RON_HUMAN RON_HUMAN] Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to MST1 ligand. Regulates many physiological processes including cell survival, migration and differentiation. Ligand binding at the cell surface induces autophosphorylation of RON on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1 or the adapter GAB1. Recruitment of these downstream effectors by RON leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. RON signaling activates the wound healing response by promoting epithelial cell migration, proliferation as well as survival at the wound site. Plays also a role in the innate immune response by regulating the migration and phagocytic activity of macrophages. Alternatively, RON can also promote signals such as cell migration and proliferation in response to growth factors other than MST1 ligand.<ref>PMID:7939629</ref> <ref>PMID:9764835</ref> <ref>PMID:18836480</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Receptor protein-tyrosine kinase]] | + | [[Category: Large Structures]] |
| - | [[Category: Chao, K L]] | + | [[Category: Chao KL]] |
| - | [[Category: Herzberg, O]] | + | [[Category: Herzberg O]] |
| - | [[Category: Growth factor receptor/growth factor]]
| + | |
| - | [[Category: Hydrolase-signaling protein complex]]
| + | |
| - | [[Category: Macrophage stimulating protein]]
| + | |
| - | [[Category: Receptor-ligand complex]]
| + | |
| - | [[Category: Ron receptor tyrosine kinase]]
| + | |
| Structural highlights
Function
RON_HUMAN Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to MST1 ligand. Regulates many physiological processes including cell survival, migration and differentiation. Ligand binding at the cell surface induces autophosphorylation of RON on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1 or the adapter GAB1. Recruitment of these downstream effectors by RON leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. RON signaling activates the wound healing response by promoting epithelial cell migration, proliferation as well as survival at the wound site. Plays also a role in the innate immune response by regulating the migration and phagocytic activity of macrophages. Alternatively, RON can also promote signals such as cell migration and proliferation in response to growth factors other than MST1 ligand.[1] [2] [3]
Publication Abstract from PubMed
Recepteur d'Origine Nantais (RON1) receptor tyrosine kinase and its ligand, serum Macrophage Stimulating Protein (MSP), play important roles in inflammation, cell growth, migration and epithelial to mesenchymal transition during tumor development. The binding of mature MSPalphabeta (disulfide-linked alpha and beta chains) to RON ectodomain modulates receptor dimerization, followed by autophosphorylation of tyrosines in the cytoplasmic receptor kinase domains. Receptor recognition is mediated by binding of MSP beta-chain (MSPbeta) to the RON Sema domain. Here we report the structure of RON Sema-PSI-IPT1 (SPI1) domains in complex with MSPbeta at 3.0 A resolution. The MSPbeta serine protease-like beta-barrel uses the degenerate serine protease active site to recognize blades 2, 3, and 4 of the beta-propeller fold of RON Sema. Despite the sequence homology between RON and MET and between MSP and HGF, it is well established that there is no cross reactivity between the two receptor-ligand systems. Comparison of the structure of RON SPI1 in complex with MSPbeta and that of MET Sema-PSI in complex with HGFbeta reveals the receptor-ligand selectivity determinants. Analytical ultracentrifugation studies of the SPI1/MSPbeta interaction confirm the formation of a 1:1 complex. SPI1 and MSPalphabeta also associate primarily as a 1:1 complex with a similar binding affinity to that of SPI1/MSPbeta. In addition, the SPI1/MSPalphabeta ultracentrifuge studies reveals a low abundance 2:2 complex with ~10-fold lower binding affinity compared with the 1:1 species. These results support the hypothesis that the alpha-chain of MSPalphabeta mediates RON dimerization.
Structural Basis for the Binding Specificity of Human RON Receptor Tyrosine Kinase to Macrophage Stimulating Protein.,Chao KL, Gorlatova NV, Eisenstein E, Herzberg O J Biol Chem. 2014 Sep 5. pii: jbc.M114.594341. PMID:25193665[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wang MH, Ronsin C, Gesnel MC, Coupey L, Skeel A, Leonard EJ, Breathnach R. Identification of the ron gene product as the receptor for the human macrophage stimulating protein. Science. 1994 Oct 7;266(5182):117-9. PMID:7939629
- ↑ Nanney LB, Skeel A, Luan J, Polis S, Richmond A, Wang MH, Leonard EJ. Proteolytic cleavage and activation of pro-macrophage-stimulating protein and upregulation of its receptor in tissue injury. J Invest Dermatol. 1998 Oct;111(4):573-81. PMID:9764835 doi:http://dx.doi.org/10.1046/j.1523-1747.1998.00332.x
- ↑ Feres KJ, Ischenko I, Hayman MJ. The RON receptor tyrosine kinase promotes MSP-independent cell spreading and survival in breast epithelial cells. Oncogene. 2009 Jan 15;28(2):279-88. doi: 10.1038/onc.2008.383. Epub 2008 Oct 6. PMID:18836480 doi:http://dx.doi.org/10.1038/onc.2008.383
- ↑ Chao KL, Gorlatova NV, Eisenstein E, Herzberg O. Structural Basis for the Binding Specificity of Human RON Receptor Tyrosine Kinase to Macrophage Stimulating Protein. J Biol Chem. 2014 Sep 5. pii: jbc.M114.594341. PMID:25193665 doi:http://dx.doi.org/10.1074/jbc.M114.594341
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