title: Effect of double mutations K214/A-E215/Q of FRATide on GSK3β: insights from molecular dynamics simulation and normal mode analysis.
abstract: Glycogen synthase kinase 3β (GSK3β) is a multifunctional serine/threonine protein kinase that is involved in several biological processes including insulin and Wnt signaling pathways. The Wnt signaling via FRAT-mediated displacement of axin inhibits GSK3β activity toward non-primed substrates without affecting its activity toward primed substrates. Herein, molecular dynamics simulation, molecular mechanics generalized Born/surface area (MM_GBSA) calculation, and normal mode analysis are performed to explore the structural influence of the double mutations K214/A-E215/Q of FRATide on the GSK3β-FRATide complex. The results reveal that the priming phosphate-binding site, the primed substrate-binding site, the alignment of the critical active site residues in the ATP-binding site, as well as the periodic open-closed conformational change of the ATP-binding site, which are critical for the catalytic activity of GSK3β, are negligibly influenced in the mutated system compared with the wild-type (WT) system. This indicates that FRATide does not inhibit the GSK3β activity toward primed substrates. Additionally, MM_GBSA calculation indicates that the less energy-favorable GSK3β-FRATide complex is observed in the mutant than in the WT complex.
authors.affiliation: Department of Chemistry, Zhejiang University, Hangzhou, 310027, Zhejiang, China. lushaoyong@yeah.net
authors.forename: Shao-Yong
authors.initials: SY
authors.lastname: Lu
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Jiang
authors.forename: Jian-Wei
authors.initials: JW
authors.lastname: Zou
authors.forename: Tian-Xing
authors.initials: TX
authors.lastname: Wu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001665:Binding Sites; D038362:Glycogen Synthase Kinase 3 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010710:Phosphates / Q000378:metabolism; D010766:Phosphorylation; D011487:Protein Conformation; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C491819:FRAT1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D010710:Phosphates; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3