Pathogenic variants in the fibronectin type III domain of leptin receptor: Molecular dynamics simulation and structural analysis

Takashi Kato; Fumiko Matsuzawa; Nobuhiro Shojima; Toshimasa Yamauchi

doi:10.1016/j.jmgm.2024.108912

Pathogenic variants in the fibronectin type III domain of leptin receptor: Molecular dynamics simulation and structural analysis

J Mol Graph Model. 2024 Nov 20:135:108912. doi: 10.1016/j.jmgm.2024.108912. Online ahead of print.

Authors

Takashi Kato¹, Fumiko Matsuzawa², Nobuhiro Shojima¹, Toshimasa Yamauchi³

Affiliations

¹ Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
² Tokyo R&D Center, Altif Laboratories, Inc., 3F Shiodome Building, 1-2-20 Kaigan, Minato-ku, Tokyo, 105-0022, Japan.
³ Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. Electronic address: tyamau@m.u-tokyo.ac.jp.

PMID: 39608136
DOI: 10.1016/j.jmgm.2024.108912

Abstract

Several case reports have identified leptin receptor (LEPR) variants associated with severe obesity in humans. However, the structure of LEPR has only been partially understood until recently, and few studies have investigated the detrimental effects of these variants on the protein's three-dimensional structure. Notably, fibronectin type III (FnIII) domains play a crucial role in signal transduction. In this study, we examined the impact of 10 variants within the FnIII domains on LEPR structure using molecular dynamics (MD) simulations and structural analysis. Our 300 ns MD simulations revealed that the C604S variant, which disrupts a key disulfide bond, significantly increased the overall root-mean-square deviation (RMSD) of the FnIII-2 and FnIII-3 domains, indicating destabilization of the interdomain rigidity required for proper signaling. Variants such as P639L, N718S, and W646C also induced abnormal bending and rotational misalignment between the FnIII domains, contributing to interdomain destabilization. Structural analysis identified folding nuclei and demonstrated that L662S, W664R, H684P, and S723F destabilize the internal domain. Variants affecting interdomain resulted in lower-than-expected damage prediction scores by bioinformatics tools. This study is expected to contribute to the elucidation of the disease-causing mechanisms of missense variants in the leptin receptor.

Keywords: Fibronectin type III domain; FoldX; Folding nucleus; Leptin receptor; Molecular dynamics; Pathogenic variant.