Partial mimicry of the microtubule binding of tau by its membrane binding

Area of Science:

• Biochemistry
• Structural Biology
• Neuroscience

Background:

• Tau is an intrinsically disordered protein (IDP) that binds to microtubules and acidic membranes.
• Both binding surfaces are negatively charged, suggesting potential mimicry in tau's interactions.
• Understanding tau's binding dynamics is crucial for neurodegenerative disease research.

Purpose of the Study:

• To investigate the dynamic binding of tau K19 to acidic membranes using molecular dynamics simulations.
• To compare tau's membrane-binding interactions with its known microtubule-binding interactions.
• To elucidate the role of specific residues in tau's binding behavior.

Main Methods:

• Molecular dynamics (MD) simulations were employed to model tau K19's interaction with an acidic membrane.
• The simulated membrane-binding patterns were validated against published Electron Paramagnetic Resonance (EPR) data.
• Residue-specific membrane contact probabilities were analyzed.

Main Results:

• Tau K19's three amphipathic helices and flanking residues tether the protein to the membrane interface.
• Simulated helix separation and positioning align with experimental EPR data.
• Specific residues, including conserved Lys and Val, exhibit similar interaction patterns with both membranes and microtubules.

Conclusions:

• Tau exhibits partial mimicry in its binding to acidic membranes compared to microtubules.
• This binding mimicry is key to tau's function in anchoring microtubules and facilitating their transfer.
• The findings provide insights into tau's dual-binding capabilities and its role in cellular processes.