Ligand-specific structural domains in the fibroblast growth factor receptor.
Two tandem immunoglobulin-like disulfide loops (Loops II and III) linked by a short connecting sequence in the ectodomain of the fibroblast growth factor receptor kinase compose the binding sites for glycosaminoglycan and fibroblast growth factor (FGF) ligands. Alternate splicing of exons IIIb and IIIc coding for the COOH-terminal half of Loop III confers high affinity for FGF-7 or FGF-2, respectively, on the fibroblast growth factor receptor ectodomain without effect on the binding of FGF-1. Here we show that a 139-amino acid fragment composed of Loop II, the inter-Loop II/III sequence, and a short segment of the NH2 terminus of Loop III is sufficient and near the minimal requirement for binding of FGF-1, FGF-2, and FGF-7. Extension of the fragment by five additional highly conserved residues (SD(P/A)QP) within a distinct constitutive structural domain (fl1) in Loop III restricts the binding of FGF-7 without effect on FGF-1 and FGF-2. Since the presence of exon IIIc in the full-length ectodomain does not change this ligand binding profile, we suggest that alternately spliced exon IIIc plays no active role in binding of the three ligands. In contrast, exon IIIb actively abrogates the restriction on the binding of FGF-7 and concurrently lowers the affinity for FGF-2.
Wang
F
F
Albert B. Alkek Institute of Biosciences and Technology, Department of Biochemistry and Biophysics, Texas A & M University, Houston 77030-3303, USA.
Kan
M
M
Xu
J
J
Yan
G
G
McKeehan
W L
WL
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D017124:Conserved Sequence; D018076:DNA, Complementary; D004151:Dipeptides / Q000737:chemistry / Q000378:metabolism; D005091:Exons; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D000882:Haplorhini; D006801:Humans; D008024:Ligands; D008961:Models, Structural; D008969:Molecular Sequence Data; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
D018076:DNA, Complementary; D004151:Dipeptides; D008024:Ligands; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors