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

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 tra

SUBMITTER: Li TT 

PROVIDER: S-EPMC8669218 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature