Reduced binding of FGF1 to mutant fibroblast growth factor receptor 3.
The activating mutation FGFR3-R248C in the D2-D3 linker region of fibroblast growth factor receptor 3 leads as germline mutation to the neonatal lethal syndrome thanatophoric dysplasia type I (TD1). As somatic mutation it has been found in cancer. We introduced into the murine FGFR3 the mutation R242C that is orthologoues to the human mutation R248C. A strong reduction in binding of the 16 and 18 kDa forms of FGF1 to the mutant receptor was found, highlighting the importance of D2-D3 linker region of FGFR3 in determination of binding affinity to ligands. Another mutant, G374R, introduced into the murine FGFR3, is orthologoues to the human mutant FGFR3-G380R, and leads to achondroplasia (ACH). The binding of the 16 kDa and 18 kDa forms of FGF1 to this mutant receptor was the same as for wild-type FGFR3 in a cell-free system, but it was reduced in living cells. The data indicate a minor changes in conformation of FGFR3-G374R receptors at the cell surface that lead to reduced binding to FGF1.
Khnykin
Denis
D
Department of Biochemistry, Institute for Cancer Research, The Norwegian Radium Hospital, University of Oslo, Norway.
Olsnes
Sjur
S
D000130:Achondroplasia / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism*; D015870:Gene Expression; D051379:Mice; D009154:Mutation; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism*; D013796:Thanatophoric Dysplasia / Q000235:genetics / Q000378:metabolism
D016220:Fibroblast Growth Factor 1; D051498:Receptor, Fibroblast Growth Factor, Type 3