Acetylation and phosphorylation processes modulate Tau's binding to microtubules: A molecular dynamics study

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Microtubule-associated protein Tau's function is crucial for neuronal health.
• Post-translational modifications (PTMs) of Tau are implicated in neurodegenerative diseases.
• Understanding PTMs' effects on Tau's interaction with microtubules is vital.

Purpose of the Study:

• To investigate the molecular effects of Tau acetylation and phosphorylation on its conformation and microtubule binding.
• To model acetylated Tau (aTau) and phosphorylated Tau (pTau) variants using molecular dynamics.
• To elucidate mechanisms of Tau dysfunction in diseases like Alzheimer's.

Main Methods:

• Utilized molecular modeling and in silico techniques.
• Generated eight aTau analogues by mutating lysine sites.
• Designed pTau analogues based on known phosphorylation sites.

Main Results:

• Acetylation and phosphorylation significantly alter Tau's electrostatics and conformation.
• These PTMs generally reduce Tau's ability to bind to microtubules.
• Altered Tau conformations hinder the microtubule-binding region (MTBR).

Conclusions:

• PTMs disrupt normal Tau function by altering its interaction with microtubules.
• In silico findings provide molecular insights into Tauopathies.
• This research may inspire new therapeutic strategies for Alzheimer's disease.