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

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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.

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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

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Acknowledgments

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

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Authors and Affiliations

  1. Department of Chemistry, Zhejiang University, Hangzhou, 310027, Zhejiang, China

    Shao-Yong Lu & Tian-Xing Wu

  2. Key Laboratory for Molecular Design and Nutrition Engineering, Ningbo Institute of Technology, Zhejiang University, Ningbo, 315104, China

    Yong-Jun Jiang & Jian-Wei Zou

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  1. Shao-Yong Lu
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Correspondence to Yong-Jun Jiang.

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Lu, SY., Jiang, YJ., Zou, JW. et al. Effect of double mutations K214/A–E215/Q of FRATide on GSK3β: insights from molecular dynamics simulation and normal mode analysis. Amino Acids 43, 267–277 (2012). https://doi.org/10.1007/s00726-011-1070-4

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