| 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
Discoidin domain receptor (DDR) is a cell-surface receptor tyrosine kinase activated by the binding of its discoidin (DS) domain to fibrillar collagen. Here, we have determined the NMR structure of the DS domain in DDR2 (DDR2-DS domain), and identified the binding site to fibrillar collagen by transferred cross-saturation experiments. The DDR2-DS domain structure adopts a distorted jellyroll fold, consisting of eight beta-strands. The collagen-binding site is formed at the interloop trench, consisting of charged residues surrounded by hydrophobic residues. The surface profile of the collagen-binding site suggests that the DDR2-DS domain recognizes specific sites on fibrillar collagen. This study provides a molecular basis for the collagen-binding mode of the DDR2-DS domain.
Structural basis of the collagen-binding mode of discoidin domain receptor 2.,Ichikawa O, Osawa M, Nishida N, Goshima N, Nomura N, Shimada I EMBO J. 2007 Sep 19;26(18):4168-76. Epub 2007 Aug 16. PMID:17703188[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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
- ↑ Ichikawa O, Osawa M, Nishida N, Goshima N, Nomura N, Shimada I. Structural basis of the collagen-binding mode of discoidin domain receptor 2. EMBO J. 2007 Sep 19;26(18):4168-76. Epub 2007 Aug 16. PMID:17703188
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