Acetylation and phosphorylation processes modulate Tau's binding to microtubules: A molecular dynamics study.
Level 5 - mechanism / opinion, no new human data
In silico molecular dynamics simulation study with no human data
PubMed 36372288 · doi:10.1016/j.bbagen.2022.130276
What was done
Computational molecular modeling and molecular dynamics simulations were used to evaluate the impact of post-translational modifications on Tau conformation, electrostatics, and microtubule binding. Eight acetylated Tau analogues with mutated harmful lysine sites and phosphorylated Tau analogues reflecting normal and Alzheimer's disease brain states were simulated in intracellular fluid and near a microtubule model.
What was found
The abstract reports no numerical values or statistical effect sizes. In silico simulations demonstrated that loss of positive lysine charges via acetylation and accumulation of negative charges via phosphorylation reduced electrostatic association with microtubule tubulins in most cases. These modifications also produced conformational shifts that hindered the microtubule-binding region and impaired expected binding.
Why it matters
This study provides atomistic-level mechanistic insights into how specific acetylation and phosphorylation events disrupt Tau-microtubule interactions, offering potential structural rationale for drug discovery targeting Alzheimer's disease.
Limits
The study is entirely computational (in silico) with no wet-lab in vitro, cellular, or in vivo biological validation reported in the abstract. No quantitative binding affinities, free energy values, or simulation durations are provided in the abstract.
Cited by
- supports Phosphorylation of the tau protein alters its charge and conformation, causing it to dissociate from microtubules and leading to neurite collapse.