FGF21 N- and C-termini play different roles in receptor interaction and activation

Yie, Junming; Hecht, Randy; Patel, Jennifer; Stevens, Jennitte; Wang, Wei; Hawkins, Nessa; Steavenson, Shirley; Smith, Steve; Winters, Dwight; Fisher, Seth; Cai, Ling; Belouski, Ed; Chen, Ching; Michaels, Mark L.; Li, Yue-Sheng; Lindberg, Richard; Wang, Minghan; Véniant, Murielle; Xu, Jing

doi:10.1016/j.febslet.2008.11.023

« Previous Next »FEBS Letters
Volume 583, Issue 1 , Pages 19-24, 5 January 2009

FGF21 N- and C-termini play different roles in receptor interaction and activation

Edited by Gianni Cesareni

Junming Yie
- Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Mail Stop 29-1-A, Thousand Oaks, CA 91320, USA
- Corresponding author. Fax: +1 805 499 0953.
Randy Hecht
- Department of Protein Science, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
Jennifer Patel
- Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Mail Stop 29-1-A, Thousand Oaks, CA 91320, USA
Jennitte Stevens
- Department of Protein Science, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
Wei Wang
- Department of Protein Science, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
Nessa Hawkins
- Department of Protein Science, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
Shirley Steavenson
- Department of Protein Science, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
Steve Smith
- Department of Protein Science, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
Dwight Winters
- Department of Protein Science, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
Seth Fisher
- Department of Protein Science, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
Ling Cai
- Department of Protein Science, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
Ed Belouski
- Department of Protein Science, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
Ching Chen
- Department of Protein Science, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
Mark L. Michaels
- Department of Protein Science, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
Yue-Sheng Li
- Department of Protein Science, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
Richard Lindberg
- Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Mail Stop 29-1-A, Thousand Oaks, CA 91320, USA
Minghan Wang
- Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Mail Stop 29-1-A, Thousand Oaks, CA 91320, USA
Murielle Véniant
- Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Mail Stop 29-1-A, Thousand Oaks, CA 91320, USA
Jing Xu
- Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Mail Stop 29-1-A, Thousand Oaks, CA 91320, USA

Received 11 September 2008; received in revised form 20 October 2008; accepted 9 November 2008. published online 05 December 2008.

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.