Article

Distal mutation V486M disrupts the catalytic activity of DPP4 by affecting the flap of the propeller domain

Teng-teng Li1,2, Cheng Peng3,4,5, Ji-qiu Wang6, Zhi-jian Xu3,4,5, Ming-bo Su1, Jia Li1,2, Wei-liang Zhu3,4,5, Jing-ya Li1
1 State Key Laboratory of Drug Research, the National Drug Screening Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
3 CAS Key Laboratory of Receptor Research
4 Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
5 School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China
6 Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200025, China
Correspondence to: Wei-liang Zhu: wlzhu@simm.ac.cn, Jing-ya Li: jyli@simm.ac.cn,
DOI: 10.1038/s41401-021-00818-x
Received: 15 August 2021
Accepted: 6 November 2021
Advance online: 14 December 2021

Abstract

Dipeptidyl peptidase-4 (DPP4) plays a crucial role in regulating the bioactivity of glucagon-like peptide-1 (GLP-1) that enhances insulin secretion and pancreatic β-cell proliferation, making it a therapeutic target for type 2 diabetes. Although the crystal structure of DPP4 has been determined, its structure-function mechanism is largely unknown. Here, we examined the biochemical properties of sporadic human DPP4 mutations distal from its catalytic site, among which V486M ablates DPP4 dimerization and causes loss of enzymatic activity. Unbiased molecular dynamics simulations revealed that the distal V486M mutation induces a local conformational collapse in a β-propeller loop (residues 234–260, defined as the flap) and disrupts the dimerization of DPP4. The “open/closed” conformational transitions of the flap whereby capping the active site, are involved in the enzymatic activity of DPP4. Further site-directed mutagenesis guided by theoretical predictions verified the importance of the conformational dynamics of the flap for the enzymatic activity of DPP4. Therefore, the current studies that combined theoretical modeling and experimental identification, provide important insights into the biological function of DPP4 and allow for the evaluation of directed DPP4 genetic mutations before initiating clinical applications and drug development.
Keywords: DPP4; distal mutation; enzymatic activity; molecular dynamics simulation; structure-function mechanism

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