Direct Observation of the Conformational Transitions in Tau and Their Correlation with Phase Behavior

Area of Science:

• Biochemistry
• Cell Biology
• Neuroscience

Background:

• Liquid-liquid phase separation (LLPS) forms dynamic membraneless organelles crucial for cellular regulation.
• Aberrant LLPS transitions are linked to neurodegenerative diseases and cancers.
• Microtubule-associated protein Tau, implicated in Alzheimer's and Parkinson's, undergoes LLPS, forming precursors to amyloid aggregates.

Purpose of the Study:

• To investigate the relationship between full-length Tau conformations and its phase separation behavior.
• To elucidate the mechanisms by which Tau's conformational state influences its propensity for LLPS.

Main Methods:

• Single-molecule Förster Resonance Energy Transfer (smFRET)
• Molecular Dynamics (MD) simulations

Main Results:

• Tau transitions between compact and extended conformations during LLPS, regardless of driving forces.
• Intramolecular interactions stabilizing monomeric Tau correlate with intermolecular interactions driving Tau LLPS.
• Tau LLPS facilitates the formation of dynamic networks.

Conclusions:

• Tau's conformational state is a key determinant of its phase separation propensity.
• Mechanistic insights into sequence-encoded structural processes driving biological phase separation.
• Understanding Tau's phase behavior provides crucial information for neurodegenerative disease research.