The crystal structure of fibroblast growth factor (FGF) 19 reveals novel features of the FGF family and offers a structural basis for its unusual receptor affinity.
The 22 members of the FGF family have been implicated in cell proliferation, differentiation, survival, and migration. They are required for both development and maintenance of vertebrates, demonstrating an exquisite pattern of affinities for both protein and proteoglycan receptors. FGF19, one of the most divergent human FGFs, is unique in binding solely to one receptor, FGFR4. We have used molecular replacement to solve the crystal structure of FGF19 at 1.3 A resolution using five superimposed FGF structures as the search model. The structure shows that two novel disulfide bonds found in FGF19, one of which appears to be conserved among several of the other FGFs, stabilize extended loops. The key heparin-binding loops of FGF19 have radically different conformations and charge patterns, compared to other FGFs, correlating with the unusually low affinity of FGF19 for heparin. A model for the complex of FGF19 with FGFR4 demonstrates that unique sequences in both FGF19 and FGFR4 are key to the formation of the complex. The structure therefore offers a clear explanation for the unusual affinity of FGF19 for FGFR4 alone.
Harmer
Nicholas J
NJ
Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, United Kingdom. nic@cryst.bioc.cam.ac.uk
Pellegrini
Luca
L
Chirgadze
Dima
D
Fernandez-Recio
Juan
J
Blundell
Tom L
TL
D000595:Amino Acid Sequence; D019295:Computational Biology / Q000379:methods; D018360:Crystallography, X-Ray; D005346:Fibroblast Growth Factors / Q000737:chemistry*; D006493:Heparin / Q000737:chemistry; D006801:Humans; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D051499:Receptor, Fibroblast Growth Factor, Type 4; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
C117476:FGF19 protein, human; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors; D006493:Heparin; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4