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| | ==Zymogen HGF-beta/MET with Zymogen Activator Peptide ZAP2.3== | | ==Zymogen HGF-beta/MET with Zymogen Activator Peptide ZAP2.3== |
| - | <StructureSection load='4o3u' size='340' side='right' caption='[[4o3u]], [[Resolution|resolution]] 3.04Å' scene=''> | + | <StructureSection load='4o3u' size='340' side='right'caption='[[4o3u]], [[Resolution|resolution]] 3.04Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4o3u]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4O3U OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4O3U FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4o3u]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4O3U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4O3U FirstGlance]. <br> |
| - | </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> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.04Å</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=4o3u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4o3u OCA], [http://pdbe.org/4o3u PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4o3u RCSB], [http://www.ebi.ac.uk/pdbsum/4o3u PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4o3u ProSAT]</span></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=4o3u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4o3u OCA], [https://pdbe.org/4o3u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4o3u RCSB], [https://www.ebi.ac.uk/pdbsum/4o3u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4o3u ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/HGF_HUMAN HGF_HUMAN]] Defects in HGF are the cause of deafness autosomal recessive type 39 (DFNB39) [MIM:[http://omim.org/entry/608265 608265]]. A form of profound prelingual sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information.<ref>PMID:19576567</ref> [[http://www.uniprot.org/uniprot/MET_HUMAN MET_HUMAN]] Note=Activation of MET after rearrangement with the TPR gene produces an oncogenic protein. Note=Defects in MET may be associated with gastric cancer. Defects in MET are a cause of hepatocellular carcinoma (HCC) [MIM:[http://omim.org/entry/114550 114550]].<ref>PMID:9927037</ref> Defects in MET are a cause of renal cell carcinoma papillary (RCCP) [MIM:[http://omim.org/entry/605074 605074]]. It is a subtype of renal cell carcinoma tending to show a tubulo-papillary architecture formed by numerous, irregular, finger-like projections of connective tissue. Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. It is subclassified into common renal cell carcinoma (clear cell, non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma.<ref>PMID:9140397</ref> <ref>PMID:9563489</ref> <ref>PMID:10433944</ref> <ref>PMID:10417759</ref> <ref>PMID:10327054</ref> Note=A common allele in the promoter region of the MET shows genetic association with susceptibility to autism in some families. Functional assays indicate a decrease in MET promoter activity and altered binding of specific transcription factor complexes. Note=MET activating mutations may be involved in the development of a highly malignant, metastatic syndrome known as cancer of unknown primary origin (CUP) or primary occult malignancy. Systemic neoplastic spread is generally a late event in cancer progression. However, in some instances, distant dissemination arises at a very early stage, so that metastases reach clinical relevance before primary lesions. Sometimes, the primary lesions cannot be identified in spite of the progresses in the diagnosis of malignancies.<ref>PMID:20949619</ref> | + | [https://www.uniprot.org/uniprot/HGF_HUMAN HGF_HUMAN] Defects in HGF are the cause of deafness autosomal recessive type 39 (DFNB39) [MIM:[https://omim.org/entry/608265 608265]. A form of profound prelingual sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information.<ref>PMID:19576567</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/HGF_HUMAN HGF_HUMAN]] Potent mitogen for mature parenchymal hepatocyte cells, seems to be a hepatotrophic factor, and acts as a growth factor for a broad spectrum of tissues and cell types. Activating ligand for the receptor tyrosine kinase MET by binding to it and promoting its dimerization.<ref>PMID:15167892</ref> <ref>PMID:20624990</ref> [[http://www.uniprot.org/uniprot/MET_HUMAN MET_HUMAN]] Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand. Regulates many physiological processes including proliferation, scattering, morphogenesis and survival. Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1, SRC, GRB2, STAT3 or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. The RAS-ERK activation is associated with the morphogenetic effects while PI3K/AKT coordinates prosurvival effects. During embryonic development, MET signaling plays a role in gastrulation, development and migration of muscles and neuronal precursors, angiogenesis and kidney formation. In adults, participates in wound healing as well as organ regeneration and tissue remodeling. Promotes also differentiation and proliferation of hematopoietic cells.<ref>PMID:1846706</ref> <ref>PMID:8182137</ref> <ref>PMID:15314156</ref> Acts as a receptor for Listeria internalin inlB, mediating entry of the pathogen into cells.<ref>PMID:1846706</ref> <ref>PMID:8182137</ref> <ref>PMID:15314156</ref> | + | [https://www.uniprot.org/uniprot/HGF_HUMAN HGF_HUMAN] Potent mitogen for mature parenchymal hepatocyte cells, seems to be a hepatotrophic factor, and acts as a growth factor for a broad spectrum of tissues and cell types. Activating ligand for the receptor tyrosine kinase MET by binding to it and promoting its dimerization.<ref>PMID:15167892</ref> <ref>PMID:20624990</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| | *[[Hepatocyte growth factor|Hepatocyte growth factor]] | | *[[Hepatocyte growth factor|Hepatocyte growth factor]] |
| - | *[[Hepatocyte growth factor receptor|Hepatocyte growth factor receptor]] | + | *[[Hepatocyte growth factor receptor 3D structures|Hepatocyte growth factor receptor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Receptor protein-tyrosine kinase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Eigenbrot, C]] | + | [[Category: Large Structures]] |
| - | [[Category: Landgraf, K E]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Steffek, M]] | + | [[Category: Eigenbrot C]] |
| - | [[Category: Receptor activation]] | + | [[Category: Landgraf KE]] |
| - | [[Category: Transferase-growth factor complex]] | + | [[Category: Steffek M]] |
| - | [[Category: Trypsin homoloy]]
| + | |
| Structural highlights
Disease
HGF_HUMAN Defects in HGF are the cause of deafness autosomal recessive type 39 (DFNB39) [MIM:608265. A form of profound prelingual sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information.[1]
Function
HGF_HUMAN Potent mitogen for mature parenchymal hepatocyte cells, seems to be a hepatotrophic factor, and acts as a growth factor for a broad spectrum of tissues and cell types. Activating ligand for the receptor tyrosine kinase MET by binding to it and promoting its dimerization.[2] [3]
Publication Abstract from PubMed
Stimulation of hepatocyte growth factor (HGF) signaling through the Met receptor is an attractive approach for promoting tissue repair and preventing fibrosis. Using structure-guided peptide phage display combined with an activity-based sorting strategy, we engineered allosteric activators of zymogen-like pro-HGF to bypass proteolytic activation and reversibly stimulate pro-HGF signaling through Met. Biochemical, structural and biological data showed that zymogen activator peptides (ZAPtides) potently and selectively bind the activation pocket within the serine protease-like beta-chain of pro-HGF and display titratable activation of pro-HGF-dependent Met signaling, leading to cell survival and migration. To further demonstrate the versatility of our ZAPtide platform, we identified allosteric activators for pro-macrophage stimulating protein and a zymogen serine protease, Protein C, which also provides evidence for target selectivity. These studies reveal that ZAPtides use molecular mimicry of the trypsin-like N-terminal insertion mechanism and establish a new paradigm for selective pharmacological activation of plasminogen-related growth factors and zymogen serine proteases.
An allosteric switch for pro-HGF/Met signaling using zymogen activator peptides.,Landgraf KE, Steffek M, Quan C, Tom J, Yu C, Santell L, Maun HR, Eigenbrot C, Lazarus RA Nat Chem Biol. 2014 May 25. doi: 10.1038/nchembio.1533. PMID:24859116[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Schultz JM, Khan SN, Ahmed ZM, Riazuddin S, Waryah AM, Chhatre D, Starost MF, Ploplis B, Buckley S, Velasquez D, Kabra M, Lee K, Hassan MJ, Ali G, Ansar M, Ghosh M, Wilcox ER, Ahmad W, Merlino G, Leal SM, Riazuddin S, Friedman TB, Morell RJ. Noncoding mutations of HGF are associated with nonsyndromic hearing loss, DFNB39. Am J Hum Genet. 2009 Jul;85(1):25-39. doi: 10.1016/j.ajhg.2009.06.003. Epub 2009 , Jul 2. PMID:19576567 doi:10.1016/j.ajhg.2009.06.003
- ↑ Stamos J, Lazarus RA, Yao X, Kirchhofer D, Wiesmann C. Crystal structure of the HGF beta-chain in complex with the Sema domain of the Met receptor. EMBO J. 2004 Jun 16;23(12):2325-35. Epub 2004 May 27. PMID:15167892 doi:10.1038/sj.emboj.7600243
- ↑ Tolbert WD, Daugherty-Holtrop J, Gherardi E, Vande Woude G, Xu HE. Structural basis for agonism and antagonism of hepatocyte growth factor. Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13264-9. Epub 2010 Jul 12. PMID:20624990 doi:10.1073/pnas.1005183107
- ↑ Landgraf KE, Steffek M, Quan C, Tom J, Yu C, Santell L, Maun HR, Eigenbrot C, Lazarus RA. An allosteric switch for pro-HGF/Met signaling using zymogen activator peptides. Nat Chem Biol. 2014 May 25. doi: 10.1038/nchembio.1533. PMID:24859116 doi:http://dx.doi.org/10.1038/nchembio.1533
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