Kinetic model for FGF, FGFR, and proteoglycan signal transduction complex assembly

被引:144
作者
Ibrahimi, OA
Zhang, FM
Hrstka, SCL
Mohammadi, M
Linhardt, RJ [1 ]
机构
[1] NYU, Sch Med, Dept Pharmacol, New York, NY 10016 USA
[2] Univ Iowa, Dept Chem & Biochem Engn, Iowa City, IA 52242 USA
[3] Rensselaer Polytech Inst, Dept Chem Biol & Chem Engn, Troy, NY 12180 USA
关键词
D O I
10.1021/bi0352320
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 current working model for fibroblast growth factor receptor (FGFR) dimerization and activation requires the assembly of a ternary complex of fibroblast growth factor (FGF), FGFR, and heparin or heparan sulfate proteoglycan (HSPG) on the plasma membrane. The recent FGF2-FGFR1-heparin crystal structure provides a detailed but static view of the FGF-FGFR-heparin complex. However, the kinetics of ternary complex assembly has yet to be investigated. Here, we characterize FGF2, FGFR1, and heparin interactions using surface plasmon resonance (SPR). Binding constants for binary FGF2/FGFR1 (K-D = 62 nM), FGF2/heparin (K-D = 39 nM), and FGFR1/heparin (K-D = 3.2 muM) interactions correlate to the magnitude of binding interface observed in the FGF2-FGFR1-heparin crystal structure. Interestingly, comparison of sensorgrams of sequential injections of FGF2 and FGFR1 and equimolar FGF2-FGFR1 injections onto a heparin neoproteoglycan surface demonstrates that FGF2 dramatically enhances the association of FGFR1 with heparin and leads us to propose a model for the stepwise assembly of a ternary FGF-FGFR-HSPG complex. The weak binding affinity of the FGFR1-heparin interaction suggests that in this model. FGFR and HSPG are unbound in the absence of FGF ligand. The availability or FGF results in formation of initial FGF-HSPG complexes, which promotes the rapid binding of FGFR and creates a ternary complex capable of undergoing dimerization and subsequent FGFR activation. In contrast, alternative models for the kinetic assembly of a ternary complex in which binary FGF-FGFR or FGFR-HSPG complexes are intermediates do not conform well with the experimental data.
引用
收藏
页码:4724 / 4730
页数:7
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