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| - | ==CRYSTAL STRUCTURE OF THE DDR2 DISCOIDIN DOMAIN BOUND TO A TRIPLE-HELICAL COLLAGEN PEPTIDE== | + | |
| - | <StructureSection load='2wuh' size='340' side='right' caption='[[2wuh]], [[Resolution|resolution]] 1.60Å' scene=''> | + | ==Crystal structure of the DDR2 discoidin domain bound to a triple- helical collagen peptide== |
| | + | <StructureSection load='2wuh' size='340' side='right'caption='[[2wuh]], [[Resolution|resolution]] 1.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2wuh]] is a 4 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=2WUH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2WUH FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2wuh]] 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=2WUH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2WUH FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=HYP:4-HYDROXYPROLINE'>HYP</scene>, <scene name='pdbligand=NLE:NORLEUCINE'>NLE</scene></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]] 1.6Å</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=2wuh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wuh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2wuh RCSB], [http://www.ebi.ac.uk/pdbsum/2wuh PDBsum]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=HYP:4-HYDROXYPROLINE'>HYP</scene>, <scene name='pdbligand=NLE:NORLEUCINE'>NLE</scene></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=2wuh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wuh OCA], [https://pdbe.org/2wuh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2wuh RCSB], [https://www.ebi.ac.uk/pdbsum/2wuh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2wuh ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Disease == |
| | + | [https://www.uniprot.org/uniprot/DDR2_HUMAN DDR2_HUMAN] Defects in DDR2 are the cause of spondyloepimetaphyseal dysplasia short limb-hand type (SEMD-SL) [MIM:[https://omim.org/entry/271665 271665]. A bone disease characterized by short-limbed dwarfism, a narrow chest with pectus excavatum, brachydactyly in the hands and feet, a characteristic craniofacial appearance and premature calcifications. The radiological findings are distinctive and comprise short long bones throughout the skeleton with striking epiphyses that are stippled, flattened and fragmented and flared, irregular metaphyses. Platyspondyly in the spine with wide intervertebral spaces is observed and some vertebral bodies are pear-shaped with central humps, anterior protrusions and posterior scalloping.<ref>PMID:20223752</ref> <ref>PMID:19110212</ref> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/DDR2_HUMAN DDR2_HUMAN] Tyrosine kinase that functions as cell surface receptor for fibrillar collagen and regulates cell differentiation, remodeling of the extracellular matrix, cell migration and cell proliferation. Required for normal bone development. Regulates osteoblast differentiation and chondrocyte maturation via a signaling pathway that involves MAP kinases and leads to the activation of the transcription factor RUNX2. Regulates remodeling of the extracellular matrix by up-regulation of the collagenases MMP1, MMP2 and MMP13, and thereby facilitates cell migration and tumor cell invasion. Promotes fibroblast migration and proliferation, and thereby contributes to cutaneous wound healing.<ref>PMID:9659899</ref> <ref>PMID:16186108</ref> <ref>PMID:16186104</ref> <ref>PMID:17665456</ref> <ref>PMID:18201965</ref> <ref>PMID:20564243</ref> <ref>PMID:20734453</ref> <ref>PMID:20004161</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/wu/2wuh_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/wu/2wuh_consurf.spt"</scriptWhenChecked> |
| | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
| - | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf]. | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2wuh ConSurf]. |
| | <div style="clear:both"></div> | | <div style="clear:both"></div> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 2wuh" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Collagen|Collagen]] | + | *[[Collagen 3D structures|Collagen 3D structures]] |
| | + | *[[Epithelial discoidin domain-containing receptor|Epithelial discoidin domain-containing receptor]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Bihan, D]] | + | [[Category: Large Structures]] |
| - | [[Category: Carafoli, F]] | + | [[Category: Bihan D]] |
| - | [[Category: Farndale, R W]] | + | [[Category: Carafoli F]] |
| - | [[Category: Hohenester, E]] | + | [[Category: Farndale RW]] |
| - | [[Category: Konitsiotis, A D]] | + | [[Category: Hohenester E]] |
| - | [[Category: Kvansakul, M]] | + | [[Category: Konitsiotis AD]] |
| - | [[Category: Leitinger, B]] | + | [[Category: Kvansakul M]] |
| - | [[Category: Stathopoulos, S]] | + | [[Category: Leitinger B]] |
| - | [[Category: Nucleotide-binding]]
| + | [[Category: Stathopoulos S]] |
| - | [[Category: Receptor-peptide complex]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Tyrosine-protein kinase]]
| + | |
| Structural highlights
Disease
DDR2_HUMAN Defects in DDR2 are the cause of spondyloepimetaphyseal dysplasia short limb-hand type (SEMD-SL) [MIM:271665. A bone disease characterized by short-limbed dwarfism, a narrow chest with pectus excavatum, brachydactyly in the hands and feet, a characteristic craniofacial appearance and premature calcifications. The radiological findings are distinctive and comprise short long bones throughout the skeleton with striking epiphyses that are stippled, flattened and fragmented and flared, irregular metaphyses. Platyspondyly in the spine with wide intervertebral spaces is observed and some vertebral bodies are pear-shaped with central humps, anterior protrusions and posterior scalloping.[1] [2]
Function
DDR2_HUMAN Tyrosine kinase that functions as cell surface receptor for fibrillar collagen and regulates cell differentiation, remodeling of the extracellular matrix, cell migration and cell proliferation. Required for normal bone development. Regulates osteoblast differentiation and chondrocyte maturation via a signaling pathway that involves MAP kinases and leads to the activation of the transcription factor RUNX2. Regulates remodeling of the extracellular matrix by up-regulation of the collagenases MMP1, MMP2 and MMP13, and thereby facilitates cell migration and tumor cell invasion. Promotes fibroblast migration and proliferation, and thereby contributes to cutaneous wound healing.[3] [4] [5] [6] [7] [8] [9] [10]
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
The discoidin domain receptors, DDR1 and DDR2, are widely expressed receptor tyrosine kinases that are activated by triple-helical collagen. They control important aspects of cell behavior and are dysregulated in several human diseases. The major DDR2-binding site in collagens I-III is a GVMGFO motif (O is hydroxyproline) that also binds the matricellular protein SPARC. We have determined the crystal structure of the discoidin domain of human DDR2 bound to a triple-helical collagen peptide. The GVMGFO motifs of two collagen chains are recognized by an amphiphilic pocket delimited by a functionally critical tryptophan residue and a buried salt bridge. Collagen binding results in structural changes of DDR2 surface loops that may be linked to the process of receptor activation. A comparison of the GVMGFO-binding sites of DDR2 and SPARC reveals a striking case of convergent evolution in collagen recognition.
Crystallographic insight into collagen recognition by discoidin domain receptor 2.,Carafoli F, Bihan D, Stathopoulos S, Konitsiotis AD, Kvansakul M, Farndale RW, Leitinger B, Hohenester E Structure. 2009 Dec 9;17(12):1573-81. PMID:20004161[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ali BR, Xu H, Akawi NA, John A, Karuvantevida NS, Langer R, Al-Gazali L, Leitinger B. Trafficking defects and loss of ligand binding are the underlying causes of all reported DDR2 missense mutations found in SMED-SL patients. Hum Mol Genet. 2010 Jun 1;19(11):2239-50. doi: 10.1093/hmg/ddq103. Epub 2010 Mar , 10. PMID:20223752 doi:10.1093/hmg/ddq103
- ↑ Bargal R, Cormier-Daire V, Ben-Neriah Z, Le Merrer M, Sosna J, Melki J, Zangen DH, Smithson SF, Borochowitz Z, Belostotsky R, Raas-Rothschild A. Mutations in DDR2 gene cause SMED with short limbs and abnormal calcifications. Am J Hum Genet. 2009 Jan;84(1):80-4. doi: 10.1016/j.ajhg.2008.12.004. Epub 2008, Dec 24. PMID:19110212 doi:10.1016/j.ajhg.2008.12.004
- ↑ Vogel W, Gish GD, Alves F, Pawson T. The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell. 1997 Dec;1(1):13-23. PMID:9659899
- ↑ Yang K, Kim JH, Kim HJ, Park IS, Kim IY, Yang BS. Tyrosine 740 phosphorylation of discoidin domain receptor 2 by Src stimulates intramolecular autophosphorylation and Shc signaling complex formation. J Biol Chem. 2005 Nov 25;280(47):39058-66. Epub 2005 Sep 26. PMID:16186108 doi:10.1074/jbc.M506921200
- ↑ Wall SJ, Werner E, Werb Z, DeClerck YA. Discoidin domain receptor 2 mediates tumor cell cycle arrest induced by fibrillar collagen. J Biol Chem. 2005 Dec 2;280(48):40187-94. Epub 2005 Sep 26. PMID:16186104 doi:10.1074/jbc.M508226200
- ↑ Xu L, Peng H, Glasson S, Lee PL, Hu K, Ijiri K, Olsen BR, Goldring MB, Li Y. Increased expression of the collagen receptor discoidin domain receptor 2 in articular cartilage as a key event in the pathogenesis of osteoarthritis. Arthritis Rheum. 2007 Aug;56(8):2663-73. PMID:17665456 doi:10.1002/art.22761
- ↑ Konitsiotis AD, Raynal N, Bihan D, Hohenester E, Farndale RW, Leitinger B. Characterization of high affinity binding motifs for the discoidin domain receptor DDR2 in collagen. J Biol Chem. 2008 Mar 14;283(11):6861-8. Epub 2008 Jan 16. PMID:18201965 doi:10.1074/jbc.M709290200
- ↑ Lin KL, Chou CH, Hsieh SC, Hwa SY, Lee MT, Wang FF. Transcriptional upregulation of DDR2 by ATF4 facilitates osteoblastic differentiation through p38 MAPK-mediated Runx2 activation. J Bone Miner Res. 2010 Nov;25(11):2489-503. doi: 10.1002/jbmr.159. PMID:20564243 doi:10.1002/jbmr.159
- ↑ Zhang Y, Su J, Yu J, Bu X, Ren T, Liu X, Yao L. An essential role of discoidin domain receptor 2 (DDR2) in osteoblast differentiation and chondrocyte maturation via modulation of Runx2 activation. J Bone Miner Res. 2011 Mar;26(3):604-17. doi: 10.1002/jbmr.225. PMID:20734453 doi:10.1002/jbmr.225
- ↑ Carafoli F, Bihan D, Stathopoulos S, Konitsiotis AD, Kvansakul M, Farndale RW, Leitinger B, Hohenester E. Crystallographic insight into collagen recognition by discoidin domain receptor 2. Structure. 2009 Dec 9;17(12):1573-81. PMID:20004161 doi:10.1016/j.str.2009.10.012
- ↑ Carafoli F, Bihan D, Stathopoulos S, Konitsiotis AD, Kvansakul M, Farndale RW, Leitinger B, Hohenester E. Crystallographic insight into collagen recognition by discoidin domain receptor 2. Structure. 2009 Dec 9;17(12):1573-81. PMID:20004161 doi:10.1016/j.str.2009.10.012
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