Microsecond Dynamics During the Binding-induced Folding of an Intrinsically Disordered Protein

Area of Science:

• Biochemistry
• Neuroscience
• Structural Biology

Background:

• Tau protein is intrinsically disordered and linked to neurodegenerative diseases.
• Tau's repeat domain (tau-K18) forms helical structures with lipids.
• Understanding tau's structural transitions is crucial for disease mechanisms.

Purpose of the Study:

• Investigate the mechanism of tau-K18 helical structure formation induced by sodium dodecyl sulfate (SDS).
• Characterize the intermediate states and kinetics of this disorder-to-order transition.
• Determine if the helical conformation is aggregation-competent.

Main Methods:

• Photoinduced electron transfer coupled to fluorescence correlation spectroscopy (PET-FCS) for conformational dynamics.
• Continuous flow mixer for microsecond kinetic measurements.
• Biophysical probes to study protein structure and interactions.

Main Results:

• Identified an intermediate state (I) in equilibrium with the unfolded state (U).
• Observed cooperative binding of SDS inducing a compact helical intermediate (IL5) within microseconds.
• Elucidated a U ↔ I ↔ IL5 ↔ FL5 mechanism for helical structure formation.
• Determined the final helical state (FL5) forms from IL5 with a time constant of 50-200 µs.

Conclusions:

• SDS at sub-micellar concentrations induces a rapid disorder-to-order transition in tau-K18.
• The helical conformation of tau-K18 is aggregation-competent.
• This mechanism provides insight into tau aggregation in neurodegenerative diseases.