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Updated: May 2, 2026
Nuclear Magnetic Resonance Spectroscopy for the Identification of Multiple Phosphorylations of Intrinsically Disordered Proteins
Published on: December 27, 2016
Molecular dynamics simulation of the phosphorylation-induced conformational changes of a tau peptide fragment
Albert J Lyons1, Neha S Gandhi, Ricardo L Mancera
1School of Biomedical Sciences, CHIRI Biosciences, Curtin University, Perth, 6845, Western Australia.
Abstract:
Aggregation of the microtubule associated protein tau (MAPT) within neurons of the brain is the leading cause of tauopathies such as Alzheimer's disease. MAPT is a phospho-protein that is selectively phosphorylated by a number of kinases in vivo to perform its biological function. However, it may become pathogenically hyperphosphorylated, causing aggregation into paired helical filaments and neurofibrillary tangles. The phosphorylation induced conformational change on a peptide of MAPT (htau225-250) was investigated by performing molecular dynamics simulations with different phosphorylation patterns of the peptide (pThr231 and/or pSer235) in different simulation conditions to determine the effect of ionic strength and phosphate charge. All phosphorylation patterns were found to disrupt a nascent terminal β-sheet pattern (226VAVVR230 and 244QTAPVP249), replacing it with a range of structures. The double pThr231/pSer235 phosphorylation pattern at experimental ionic strength resulted in the best agreement with NMR structural characterization, with the observation of a transient α-helix (239AKSRLQT245). PPII helical conformations were only found sporadically throughout the simulations.
Insights
Microtubule-associated protein tau (MAPT) phosphorylation drives tauopathies like Alzheimer's disease. Molecular dynamics simulations reveal how specific phosphorylation patterns alter MAPT structure, impacting aggregation and disease progression.
Area of Science:
- Neuroscience
- Biochemistry
- Computational Biology
Background:
- Microtubule-associated protein tau (MAPT) aggregation in neurons causes tauopathies, including Alzheimer's disease.
- MAPT is a phosphoprotein; pathological hyperphosphorylation leads to neurofibrillary tangles.
- Understanding phosphorylation-induced structural changes is crucial for therapeutic development.
Purpose of the Study:
- To investigate the conformational changes of a MAPT peptide (htau225-250) induced by phosphorylation.
- To determine the effects of different phosphorylation patterns (pThr231 and/or pSer235) and simulation conditions (ionic strength, phosphate charge) on MAPT structure.
Main Methods:
- Utilized molecular dynamics simulations.
- Simulated the htau225-250 peptide with various phosphorylation patterns (pThr231, pSer235, double phosphorylation).
- Varied simulation conditions including ionic strength and phosphate charge.
Main Results:
- All phosphorylation patterns disrupted nascent terminal β-sheet structures (226VAVVR230 and 244QTAPVP249).
- The double pThr231/pSer235 phosphorylation pattern at experimental ionic strength best matched NMR data.
- Observed a transient α-helix (239AKSRLQT245) under specific phosphorylation and ionic strength conditions.
Conclusions:
- Phosphorylation significantly alters MAPT peptide conformation, disrupting β-sheet formation.
- The double phosphorylation pattern (pThr231/pSer235) under physiological ionic strength shows good agreement with experimental data.
- These findings provide insights into the structural basis of tauopathy pathogenesis.
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