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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This work was supported by the Natural Science Foundation of China (No.20803063).
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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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DOI: https://doi.org/10.1007/s00726-011-1070-4