1si5

From Proteopedia

(Difference between revisions)

Revision as of 07:35, 6 January 2015

Protease-like domain from 2-chain hepatocyte growth factor

Structural highlights

1si5 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:	FirstGlance, OCA, RCSB, PDBsum

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]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Hepatocyte growth factor (HGF), a plasminogen-related growth factor, is the ligand for Met, a receptor tyrosine kinase implicated in development, tissue regeneration, and invasive tumor growth. HGF acquires signaling activity only upon proteolytic cleavage of single-chain HGF into its alpha/beta heterodimer, similar to zymogen activation of structurally related serine proteases. Although both chains are required for activation, only the alpha-chain binds Met with high affinity. Recently, we reported that the protease-like HGF beta-chain binds to Met with low affinity (Stamos, J., Lazarus, R. A., Yao, X., Kirchhofer, D., and Wiesmann, C. (2004) EMBO J. 23, 2325-2335). Here we demonstrate that the zymogen-like form of HGF beta also binds Met, albeit with 14-fold lower affinity than the protease-like form, suggesting optimal interactions result from conformational changes upon cleavage of the single-chain form. Extensive mutagenesis of the HGF beta region corresponding to the active site and activation domain of serine proteases showed that 17 of the 38 purified two-chain HGF mutants resulted in impaired cell migration or Met phosphorylation but no loss in Met binding. However, reduced biological activities were well correlated with reduced Met binding of corresponding mutants of HGF beta itself in assays eliminating dominant alpha-chain binding contributions. Moreover, the crystal structure of HGF beta determined at 2.53 A resolution provides a structural context for the mutagenesis data. The functional Met binding site is centered on the "active site region" including "triad" residues Gln(534) [c57], Asp(578) [c102], and Tyr(673) [c195] and neighboring "activation domain" residues Val(692), Pro(693), Gly(694), Arg(695), and Gly(696) [c214-c219]. Together they define a region that bears remarkable resemblance to substrate processing regions of serine proteases. Models of HGF-dependent Met receptor activation are discussed.

Structural and functional basis of the serine protease-like hepatocyte growth factor beta-chain in Met binding and signaling.,Kirchhofer D, Yao X, Peek M, Eigenbrot C, Lipari MT, Billeci KL, Maun HR, Moran P, Santell L, Wiesmann C, Lazarus RA J Biol Chem. 2004 Sep 17;279(38):39915-24. Epub 2004 Jun 24. PMID:15218027^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ Kirchhofer D, Yao X, Peek M, Eigenbrot C, Lipari MT, Billeci KL, Maun HR, Moran P, Santell L, Wiesmann C, Lazarus RA. Structural and functional basis of the serine protease-like hepatocyte growth factor beta-chain in Met binding and signaling. J Biol Chem. 2004 Sep 17;279(38):39915-24. Epub 2004 Jun 24. PMID:15218027 doi:http://dx.doi.org/10.1074/jbc.M404795200

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1si5"

@@ Line 3: / Line 3: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[1si5]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1SI5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1SI5 FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1si5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1si5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1si5 RCSB], [http://www.ebi.ac.uk/pdbsum/1si5 PDBsum]</span></td></tr>
+</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=1si5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1si5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1si5 RCSB], [http://www.ebi.ac.uk/pdbsum/1si5 PDBsum]</span></td></tr>
-<table>
+</table>
 == 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>
@@ Line 35: / Line 35: @@
 </StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Billeci, K L.]]
+[[Category: Billeci, K L]]
-[[Category: Eigenbrot, C.]]
+[[Category: Eigenbrot, C]]
-[[Category: Kirchhofer, D.]]
+[[Category: Kirchhofer, D]]
-[[Category: Lazarus, R A.]]
+[[Category: Lazarus, R A]]
-[[Category: Lipari, M T.]]
+[[Category: Lipari, M T]]
-[[Category: Maun, H R.]]
+[[Category: Maun, H R]]
-[[Category: Moran, P.]]
+[[Category: Moran, P]]
-[[Category: Peek, M.]]
+[[Category: Peek, M]]
-[[Category: Santell, L.]]
+[[Category: Santell, L]]
-[[Category: Yao, X.]]
+[[Category: Yao, X]]
 [[Category: Chymotrypsin homology]]
 [[Category: Hormone-growth factor complex]]

1si5

From Proteopedia

Revision as of 07:35, 6 January 2015

Protease-like domain from 2-chain hepatocyte growth factor

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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