Mapping of epitopes in discoidin domain receptor 1 critical for collagen binding

被引:66
作者
Curat, CA
Eck, M
Dervillez, X
Vogel, WF
机构
[1] Goethe Univ Frankfurt, Georg Speyer Haus Inst Biomed Res, Lab Extracellular Matrix Signaling & Tumor Invas, D-60596 Frankfurt, Germany
[2] Goethe Univ Frankfurt, Georg Speyer Haus Inst Biomed Res, Dept Infect Dis, D-60596 Frankfurt, Germany
关键词
D O I
10.1074/jbc.M104360200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The binding and activation of the discoidin domain receptor I by collagen has led to the conclusion that proteins from the extracellular matrix can directly induce receptor tyrosine kinase-mediated signaling cascades. A region in the extracellular domain of DDR1 homologous to the Dictyostelium discoideum protein discoidin-I is also present in the secreted human protein RS1. Mutations in RS1 cause retinoschisis, a genetic disorder characterized by ablation of the retina. By introducing point mutations into the discoidin domain of DDR1 at positions homologous to the retinoschisis mutations, ligand binding epitopes in the discoidin domain of DDR1 were mapped. Surprisingly, some residues only affected receptor phosphorylation, whereas others influenced both collagen-binding and receptor activation. Furthermore, two truncated DDR1 variants, lacking either the discoidin domain or the stalk region between the discoidin and transmembrane domain, were generated. We showed that (i) the discoidin domain was necessary and sufficient for collagen binding, (ii) only the region between discoidin and transmembrane domain was glycosylated, and (iii) the entire extracellular domain was essential for transmembrane signaling. Using these results, we were able to predict key sites in the collagen-binding epitope of DDR1 and to suggest a potential mechanism of signaling.
引用
收藏
页码:45952 / 45958
页数:7
相关论文
共 51 条
  • [11] DIMARCO E, 1993, J BIOL CHEM, V268, P24290
  • [12] Crystal structure of the I domain from integrin alpha 2 beta 1
    Emsley, J
    King, SL
    Bergelson, JM
    Liddington, RC
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (45) : 28512 - 28517
  • [13] Structural basis of collagen recognition by integrin α2β1
    Emsley, J
    Knight, CG
    Farndale, RW
    Barnes, MJ
    Liddington, RC
    [J]. CELL, 2000, 101 (01) : 47 - 56
  • [14] Discoidin domain receptor 1 (DDR1) signaling in PC12 cells: activation of juxtamembrane domains in PDGFR/DDR/TrkA chimeric receptors
    Foehr, ED
    Tatavos, A
    Tanabe, E
    Raffioni, S
    Goetz, S
    Dimarco, E
    De Luca, M
    Bradshaw, RA
    [J]. FASEB JOURNAL, 2000, 14 (07) : 973 - 981
  • [15] Clinical features in affected males with X-linked retinoschisis
    George, NDL
    Yates, JRW
    Moore, AT
    [J]. ARCHIVES OF OPHTHALMOLOGY, 1996, 114 (03) : 274 - 280
  • [16] Retinoschisin, the X-linked retinoschisis protein, is a secreted photoreceptor protein, and is expressed and released by Weri-Rb1 cells
    Grayson, C
    Reid, SNM
    Ellis, JA
    Rutherford, A
    Sowden, JC
    Yates, JRW
    Farber, DB
    Trump, D
    [J]. HUMAN MOLECULAR GENETICS, 2000, 9 (12) : 1873 - 1879
  • [17] Hiriyanna KT, 1999, HUM MUTAT, V14, P423, DOI 10.1002/(SICI)1098-1004(199911)14:5<423::AID-HUMU8>3.0.CO
  • [18] 2-D
  • [19] The discoidin domain receptor tyrosine kinase DDR1 in arterial wound repair
    Hou, GP
    Vogel, W
    Bendeck, MP
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 2001, 107 (06) : 727 - 735
  • [20] Jansson M, 2001, J CELL SCI, V114, P2043