Premium
Insights into unbinding mechanisms upon two mutations investigated by molecular dynamics study of GSK3β–axin complex: Role of packing hydrophobic residues
Author(s) -
Zhang Na,
Jiang Yongjun,
Zou Jianwei,
Zhuang Shulin,
Jin Haixiao,
Yu Qingsen
Publication year - 2007
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.21359
Subject(s) - wnt signaling pathway , mutant , gsk 3 , molecular dynamics , chemistry , scaffold protein , biophysics , kinase , microbiology and biotechnology , biochemistry , biology , signal transduction , gene , computational chemistry
Glycogen synthase kinase 3β (GSK 3β) is a key component of several cellular processes including Wnt and insulin signalling pathways. The interaction of GSK3β with scaffolding peptide axin is thought to be responsible for the effective phosphorylation of β‐catenin, the core effector of Wnt signaling, which has been linked with the occurrence of colon cancer and melanoma. It has been demonstrated that the binding of axin to GSK3β is abolished by the single‐point mutation of Val267 to Gly (V267G) in GSK3β or Leu392 to Pro (L392P) in axin. Molecular dynamics (MD) simulations were performed on wild type (WT), V267G mutant and L392P one to elucidate the two unbinding mechanisms that occur through different pathways. Besides, rough energy and residue‐based energy decomposition were calculated by MM_GBSA (molecular mechanical Generalized_Born surface area) approach to illuminate the instability of the two mutants. The MD simulations of the two mutants and WT reveal that the structure of GSK3β remains unchanged, while axin moves away from the interfacial hydrophobic pockets in both two mutants. Axin exhibits positional shift in V267G mutant, whereas, losing the hydrogen bonds that are indispensable for stabilizing the helix structure of wild type axin, the helix of axin is distorted in L392P mutant. To conclude, both two mutants destroy the hydrophobic interaction that is essential to the stability of GSK3β‐axin complex. Proteins 2007. © 2007 Wiley‐Liss, Inc.