Conformation-based assay of tau protein aggregation

Area of Science:

• Biochemistry
• Neuroscience
• Structural Biology

Background:

• Amyloid fiber formation is linked to neurodegenerative diseases like Alzheimer's.
• The protein tau, an intrinsically disordered protein (IDP), is implicated in neurofibrillary tangle formation.
• Understanding tau aggregation mechanisms, especially early conformational changes, is crucial for disease pathology.

Purpose of the Study:

• To investigate the role of conformational changes in tau protein aggregation.
• To demonstrate a method for assaying structural changes in IDPs during aggregation.
• To characterize early conformational shifts in tau's aggregation-prone regions.

Main Methods:

• Utilizing double spin labeling of tau's β-sheet stacking region.
• Employing pulsed double electron-electron resonance (PELDOR) spectroscopy.
• Probing intramolecular distances within aggregation-prone domains of tau.

Main Results:

• Demonstrated that double spin labeling and PELDOR can detect conformational changes in tau during aggregation.
• Observed a conformational rearrangement in the PHF6* segment of tau.
• Identified an early-stage, on-pathway shift towards an 'opening' of the PHF6* conformation.

Conclusions:

• Double spin labeling with PELDOR is a powerful technique for studying conformational dynamics of IDPs during aggregation.
• Early conformational opening of the PHF6* segment is a key event in tau aggregation.
• This methodology can be applied to other aggregation-prone segments of tau and other IDPs.