Multivalency in Tau-Microtubule Interactions: Heterogeneous Association and Functional Implications

Area of Science:

• Neuroscience
• Biophysics
• Computational Biology

Background:

• Tau is a crucial microtubule-associated protein for neuronal function.
• Tau's disordered nature and multivalent binding present structural characterization challenges.
• Electrostatic interactions govern tau's dynamic behavior with microtubules.

Purpose of the Study:

• Investigate tau-microtubule (MT) interactions using simulations.
• Understand how tau's multivalent binding is regulated at the sub-regional level.
• Explore the impact of isoform variation and phosphorylation on tau-MT binding.

Main Methods:

• Coarse-grained molecular dynamics simulations.
• Modeling tau interactions with tubulin C-terminal tails and structured surfaces.
• Analyzing electrostatic contributions to binding affinity and dynamics.

Main Results:

• Distinct tau sub-regions differentially contribute to tubulin binding.
• Isoform variations modulate tau-MT interactions and influence MT stability.
• Alzheimer's-associated phosphorylation weakens tau's multivalent engagement with MTs.

Conclusions:

• Electrostatics and sub-regional composition dynamically regulate tau-MT interactions.
• Findings offer mechanistic insights into tauopathy and neuronal dysfunction.
• Tau's interaction with microtubules is sensitive to phosphorylation and isoform structure.