Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization.
The crystal structure of a dimeric 2:2:2 FGF:FGFR:heparin ternary complex at 3 A resolution has been determined. Within each 1:1 FGF:FGFR complex, heparin makes numerous contacts with both FGF and FGFR, thereby augmenting FGF-FGFR binding. Heparin also interacts with FGFR in the adjoining 1:1 FGF:FGFR complex to promote FGFR dimerization. The 6-O-sulfate group of heparin plays a pivotal role in mediating both interactions. The unexpected stoichiometry of heparin binding in the structure led us to propose a revised model for FGFR dimerization. Biochemical data in support of this model are also presented. This model provides a structural basis for FGFR activation by small molecule heparin analogs and may facilitate the design of heparin mimetics capable of modulating FGF signaling.
Schlessinger
J
J
Department of Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
Plotnikov
A N
AN
Ibrahimi
O A
OA
Eliseenkova
A V
AV
Yeh
B K
BK
Yayon
A
A
Linhardt
R J
RJ
Mohammadi
M
M
D001665:Binding Sites; D003461:Crystallography; D019281:Dimerization; D005346:Fibroblast Growth Factors / Q000737:chemistry* / Q000378:metabolism; D006493:Heparin / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry* / Q000378:metabolism; D013431:Sulfates / Q000737:chemistry / Q000378:metabolism
D017468:Receptors, Fibroblast Growth Factor; D013431:Sulfates; D005346:Fibroblast Growth Factors; D006493:Heparin