title: FGF21 N- and C-termini play different roles in receptor interaction and activation.
abstract: Fibroblast growth factor-21 (FGF21) signaling requires the presence of beta-Klotho, a co-receptor with a very short cytoplasmic domain. Here we show that FGF21 binds directly to beta-Klotho through its C-terminus. Serial C-terminal truncations of FGF21 weakened or even abrogated its interaction with beta-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 beta-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 beta-Klotho and the N-terminus is critical for fibroblast growth factor receptor (FGFR) activation.
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA 91320, USA. jyie@amgen.com
authors.forename: Junming
authors.initials: J
authors.lastname: Yie
authors.forename: Randy
authors.initials: R
authors.lastname: Hecht
authors.forename: Jennifer
authors.initials: J
authors.lastname: Patel
authors.forename: Jennitte
authors.initials: J
authors.lastname: Stevens
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Nessa
authors.initials: N
authors.lastname: Hawkins
authors.forename: Shirley
authors.initials: S
authors.lastname: Steavenson
authors.forename: Steve
authors.initials: S
authors.lastname: Smith
authors.forename: Dwight
authors.initials: D
authors.lastname: Winters
authors.forename: Seth
authors.initials: S
authors.lastname: Fisher
authors.forename: Ling
authors.initials: L
authors.lastname: Cai
authors.forename: Ed
authors.initials: E
authors.lastname: Belouski
authors.forename: Ching
authors.initials: C
authors.lastname: Chen
authors.forename: Mark L
authors.initials: ML
authors.lastname: Michaels
authors.forename: Yue-Sheng
authors.initials: YS
authors.lastname: Li
authors.forename: Richard
authors.initials: R
authors.lastname: Lindberg
authors.forename: Minghan
authors.initials: M
authors.lastname: Wang
authors.forename: Murielle
authors.initials: M
authors.lastname: Véniant
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D005346:Fibroblast Growth Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D000090265:Klotho Proteins; D008156:Luciferases / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism*
chemical_list: C538995:KLB protein, human; D008565:Membrane Proteins; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D008156:Luciferases; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D000090265:Klotho Proteins