![Sample our Bioscience journals, sign in here to start your access, Latest two full volumes FREE to you for 14 days]({"type":"image" , "src" : "/sda/5925/TOC-Subject-Sample-2021-Bioscience.jpg"})
Abstract
The autoinhibition phenomenon has been frequently observed in enzymes and represents an important regulatory strategy to fine-tune enzyme activity. Evolution has exploited this mechanism to reduce enzymatic activity. Glycogen synthase kinase 3β (GSK3β) undergoes autoinhibition via the phosphorylation of Ser9 at the N-terminus of the kinase, which, acting as a pseudosubstrate, occupies the catalytic domain of GSK3β and subsequently blocks primed substrates from having access to the catalytic domain. The detailed structural basis of the autoinhibition mechanism of GSK3β by the pseudosubstrate, however, has not yet been fully resolved. Here, a three-dimensional model of the binary GSK3β-pseudosubstrate complex was built via the molecular modeling method. Based on the constructed model, extensive molecular dynamics (MD) simulations and subsequent molecular mechanics generalized Born/surface area (MM_GBSA) calculations were performed on the wild-type GSK3β-pseudosubstrate complex and three mutated systems (R4A, R6A, and S9A). Analyses of MD simulations and binding free energies revealed that the phosphorylation of Ser9 is the prerequisite for the autoinhibition of GSK3β, and both mutations of Arg4 and Arg6 to alanine markedly reduced the binding affinities of the mutated pseudosubstrate to the GSK3β catalytic domain, thereby disrupting the autoinhibition of the kinase. This study highlights the importance of Ser9, Arg6, and Arg4 in modulating the autoinhibition mechanism of GSK3β, contributing to a deeper understanding of GSK3β biology.
Communicated by Ramaswamy H. Sarma
Disclosure statement
No potential conflicts of interest were reported by the authors.