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Amino Acids

, Volume 43, Issue 1, pp 267–277 | Cite as

Effect of double mutations K214/A–E215/Q of FRATide on GSK3β: insights from molecular dynamics simulation and normal mode analysis

  • Shao-Yong Lu
  • Yong-Jun JiangEmail author
  • Jian-Wei Zou
  • Tian-Xing Wu
Original Article

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.

Keywords

GSK3β Wnt signaling MD simulation MM_GBSA Normal mode analysis 

Abbreviations

MD

Molecular dynamics

GSK3

Glycogen synthase kinase 3

GS

Glycogen synthase

APC

Adenomatous polyposis coil protein

FRAT

Advanced T-cell lymphomas protein

CDK2

Cyclin-dependent kinase 2

MAP

Mitogen-activated protein kinase

eIF2B

Eukaryotic initialization factor 2B

CREB

cAMP-responsive element-binding protein

Tau

Microtubule-binding protein

GBP

GSK3-binding protein

KE

Lysine and glutamic acid

AQ

Alanine and glutamine

NMA

Normal mode analysis

MM_GBSA

Molecular mechanics generalized born/surface area

PDB

Protein data bank

RMSD

Root mean-square deviation

Notes

Acknowledgments

This work was supported by the Natural Science Foundation of China (No.20803063).

Supplementary material

726_2011_1070_MOESM1_ESM.doc (46 kb)
Supplementary material 1 (DOC 46 kb)
726_2011_1070_MOESM2_ESM.avi (2.3 mb)
Supplementary material 2 (AVI 2365 kb)
726_2011_1070_MOESM3_ESM.avi (1.9 mb)
Supplementary material 3 (AVI 1991 kb)

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Shao-Yong Lu
    • 1
  • Yong-Jun Jiang
    • 2
    Email author
  • Jian-Wei Zou
    • 2
  • Tian-Xing Wu
    • 1
  1. 1.Department of ChemistryZhejiang UniversityHangzhouChina
  2. 2.Key Laboratory for Molecular Design and Nutrition EngineeringNingbo Institute of Technology, Zhejiang UniversityNingboChina

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