Monte Carlo Simulations of Tau Proteins: Effect of Phosphorylation

Abstract

We perform Monte Carlo simulations of tau proteins bound to a cylinder that mimics a microtubule (MT), and then study them in solution. Tau protein binds to a highly anionic MT surface to stabilize the cylindrical structure of MT. The negatively charged tail domain floats away from the anionic MT surface while positively charged tau segments localize near the MT surface. Monte Carlo simulations demonstrate that, in 3RS tau isoform (which has three imperfect repeats (R) short (S) isoform), amino acids are more condensed near a highly charged interface compared to 4RL isoform (which has four imperfect repeats (R) long (L) isoform). In 4RL isoform, amino acids in tail domain stay mostly apart from the MT surface. In the bulk solution, dephosphorylated taus are separated due to Coulomb repulsion between similarly charged isoforms. Moderate phosphorylation of 3RS isoform decreases average intermolecular distance between dephosphorylated and phosphorylated taus and lead to their overlap. Further phosphorylation does not change noticeably the intermolecular distances.

Direct force measurements reveal that protein Tau confers short-range attractions and isoform-dependent steric stabilization to microtubules

“…To model the contribution of Tau isoforms with longer PDs (because the short PD showed no appreciable change in P B ) to the MT-MT interaction potential energy, we considered the overall anionic PD of the NTT (Fig. 1B) to be extended away from the negative MT surface, with the remaining weakly positive PRR of the NTT being very weakly bound in a pancake-like conformation (61) near the surface [consistent with NMR spectroscopy (31)] with a height of ∼1 nm, in agreement with simulation (62,63) and atomic-force microscopy (64). The PRR, MT binding region, and CTT were taken to contribute to the overall charge of αβ-tubulin dimers.…”

The Many Faces of Tau

“…Tau's ability to bind microtubules depends on the MBD and on adjacent regions (Gustke et al, 1994). The tandem repeat sequences within the MBD are thought to directly bind microtubules through their positive net charge, which interacts with negatively charged residues in tubulin (Jho et al, 2010; Kar et al, 2003; Lee et al, 1988). Phosphorylation of tau regulates its binding to microtubules and is also associated with tau aggregation in disease.…”

CD64-directed microtubule associated protein tau kills leukemic blastsex vivo

“…MAP binds to microtubules via microtubule-binding repeats and enhances the stability of microtubule polymers [21–23]. Native MAP is regulated by phosphorylation at two sites to induce its dissociation and allow microtubule disassembly after mitosis, so the cytotoxic version of MAP was mutated to remove these sites (S156A and S204A) [18].…”