The Glycine Box: A Determinant of Specificity for Fibroblast Growth Factor
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- 作者：Yongde Luo ; Weiqin Lu ; Khalid A. Mohamedali ; Jun-Hyeog Jang ; Richard B. Jones ; Jerome L. Gabriel ; Mikio Kan ; and Wallace L. McKeehan
- 刊名：Biochemistry
- 出版年：1998
- 出版时间：November 24, 1998
- 年：1998
- 卷：37
- 期：47
- 页码：16506 - 16515
- 全文大小：213K
- 年卷期：v.37,no.47(November 24, 1998)
- ISSN：1520-4995
文摘
Acidic fibroblast growth factor (FGF-1), keratinocyte growth factor (FGF-7), and FGF-10 arehomologues with distinct specificity. In the presence of heparin, FGF-1 binds and activates in vitro allFGFR subtypes, while FGF-7 exhibits absolute specificity for the IIIb splice variant of FGFR2. FGF-10exhibits a similar specificity but also binds the FGFR1IIIb isoform. Neither FGF-7 nor FGF-10 will bindto IIIc isoforms of FGFR. Molecular models of FGF, heparin, and the FGFR ectodomain suggested thatsequences between 
-strands 10 and 12 of FGF may be important for the interaction of FGF with theheparin-FGFR ectodomain duplex. Site-directed mutants of FGF-7 and FGF-10 were prepared to testwhether this domain might underlie failure of FGF-7 and FGF-10 to bind to the FGFRIIIc isoforms.Constructions with substitution of FGF-1 sequences spanning the entire C-terminus encoded in exon 3 oronly C-terminal sequences spanning -strands 10 through 12 conferred ability on FGF-7 to bind to andactivate FGFRIIIc without a significant loss in binding to or activation of FGFR2IIIb. A series of twelvedifferent substitutions of shorter segments of FGF-1 sequences into the C-terminal portion of FGF-7 orFGF-10 revealed that substitution of GSCKRG for GIPVRG or the tri-peptide sequence KKN for NQKjust N-terminal to it conferred dual activities on both the FGF-7 and FGF-10 backbones. The resultssuggest that the combined sequence domain, which we call the FGF glycine box (G-box), is a majordeterminant for the specificity of the binding of FGF to heparan sulfate-FGFR duplexes.
-strands 10 and 12 of FGF may be important for the interaction of FGF with theheparin-FGFR ectodomain duplex. Site-directed mutants of FGF-7 and FGF-10 were prepared to testwhether this domain might underlie failure of FGF-7 and FGF-10 to bind to the FGFRIIIc isoforms.Constructions with substitution of FGF-1 sequences spanning the entire C-terminus encoded in exon 3 oronly C-terminal sequences spanning -strands 10 through 12 conferred ability on FGF-7 to bind to andactivate FGFRIIIc without a significant loss in binding to or activation of FGFR2IIIb. A series of twelvedifferent substitutions of shorter segments of FGF-1 sequences into the C-terminal portion of FGF-7 orFGF-10 revealed that substitution of GSCKRG for GIPVRG or the tri-peptide sequence KKN for NQKjust N-terminal to it conferred dual activities on both the FGF-7 and FGF-10 backbones. The resultssuggest that the combined sequence domain, which we call the FGF glycine box (G-box), is a majordeterminant for the specificity of the binding of FGF to heparan sulfate-FGFR duplexes.