Dynamic folding modulation generates FGF21 variant against diabetes. (9th December 2020)

• Record Type: Journal Article
• Authors: Zhu, Lei; Zhao, Hongxin; Liu, Juanjuan; Cai, Hao; Wu, Bo; Liu, Zhijun; Zhou, Shu; Liu, Qingsong; Li, Xiaokun; Bao, Bin; Liu, Jian; Dai, Han; Wang, Junfeng
• Is Part Of: EMBO reports. Volume 22:Number 1(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-09
• Subjects: anti‐diabetes -- disulfide bond mutation -- FGF21 -- folding dynamics -- NMR; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.202051352
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: Fibroblast growth factor 21 (FGF21) is a regulator of glucose and lipid metabolism. It has been widely considered as a promising candidate for the treatment of type 2 diabetes mellitus (T2DM) and other related metabolic disorders. However, lack of structural and dynamic information has limited FGF21‐based drug development. Here, using nuclear magnetic resonance (NMR) spectroscopy, we determine the structure of FGF21 and find that its non‐canonical flexible β‐trefoil conformation affects the folding of β2‐β3 hairpin and further overall protein stability. To modulate folding dynamics, we designed an FGF21‐FGF19 chimera, FGF21 SS . As expected, FGF21 SS shows better thermostability without inducing hepatocyte proliferation. Functional characterization of FGF21 SS shows its better insulin sensitivity, reduced inflammation in 3T3‐L1 adipocytes, and lower blood glucose and insulin levels in ob/ob mice compared with wild type. Our dynamics‐based rational design provides a promising approach for FGF21‐based therapeutic development against T2DM. Synopsis: NMR structural analysis of FGF21 reveals a flexible conformation that affects heparan sulfate binding and β2‐β3 hairpin folding dynamics. A folding dynamic modulated variant, FGF21SS, improves protein thermostability and anti‐diabetic activity. FGF21 structure reveals a non‐canonical flexible β‐trefoil conformation that is unfavorable for heparan sulfate and receptor interaction. The untypical β10‐β11 region of FGF21 affects the folding dynamics of the β2‐β3 hairpin and overall protein stability. Dynamic folding modulation of the β2‐β3 hairpin by SS bond mutation and loop replacement improves FGF21 variant's thermostability and anti‐diabetic activity. Abstract : NMR structural analysis of FGF21 reveals a flexible conformation that affects heparan sulfate binding and β2‐β3 hairpin folding dynamics. A folding dynamic modulated variant, FGF21SS, improves protein thermostability and anti‐diabetic activity.