1. FGF21 N- and C-termini play different roles in receptor interaction and activation
- Author
-
Seth Fisher, Ching Chen, Ling Cai, Nessa Hawkins, Shirley Steavenson, Minghan Wang, Murielle M. Véniant, Dwight Winters, Ed Belouski, Steve Smith, Mark Leo Michaels, Junming Yie, Randy Ira Hecht, Yue-Sheng Li, Wei Wang, Richard A. Lindberg, Jennifer Patel, Jennitte Stevens, and Jing Xu
- Subjects
MAPK/ERK pathway ,Molecular Sequence Data ,Fibroblast growth factor-21 ,Biophysics ,Biology ,Fibroblast growth factor ,urologic and male genital diseases ,Biochemistry ,Cell Line ,β-Klotho ,Genes, Reporter ,Structural Biology ,Genetics ,medicine ,Humans ,Amino Acid Sequence ,Receptor, Fibroblast Growth Factor, Type 1 ,Luciferases ,Fibroblast ,Receptor ,Klotho Proteins ,Molecular Biology ,Fibroblast growth factor receptor 2 ,Membrane Proteins ,Cell Biology ,Fibroblast growth factor receptor 4 ,Partial agonist ,Fibroblast growth factor receptor 3 ,Molecular biology ,female genital diseases and pregnancy complications ,Fibroblast growth factor receptor ,Protein Structure, Tertiary ,Cell biology ,Fibroblast Growth Factors ,medicine.anatomical_structure - Abstract
Fibroblast growth factor-21 (FGF21) signaling requires the presence of β-Klotho, a co-receptor with a very short cytoplasmic domain. Here we show that FGF21 binds directly to β-Klotho through its C-terminus. Serial C-terminal truncations of FGF21 weakened or even abrogated its interaction with β-Klotho in a Biacore assay, and led to gradual loss of potency in a luciferase reporter assay but with little effect on maximal response. In contrast, serial N-terminal truncations of FGF21 had no impact on β-Klotho binding. Interestingly, several of them exhibited characteristics of partial agonists with minimal effects on potency. These data demonstrate that the C-terminus of FGF21 is critical for binding to β-Klotho and the N-terminus is critical for fibroblast growth factor receptor (FGFR) activation.Structured summaryMINT-6799939: FGFR1c (uniprotkb:P11362) binds (MI:0407) to β-Klotho (uniprotkb: Q86Z14) by surface plasmon resonance (MI:0107)MINT-6799907, MINT-6799922: FGF21 (uniprotkb: Q9NSA1) binds (MI:0407) to β-Klotho (uniprotkb: Q86Z14) by surface plasmon resonance (MI:0107)
- Full Text
- View/download PDF