Transient Secondary and Tertiary Structure Formation Kinetics in the Intrinsically Disordered State of α-Synuclein...

Area of Science:

• Biochemistry
• Structural Biology
• Neuroscience

Background:

• Alpha-synuclein (aS) is a key intrinsically disordered protein (IDP) implicated in neurodegenerative diseases.
• The native state of aS is characterized by transient secondary structures rather than a stable fold.
• Understanding the kinetics of aS folding and aggregation is crucial for therapeutic development.

Purpose of the Study:

• To investigate the kinetics that prevent ordering and pathogenic beta-sheet aggregation in aS.
• To elucidate the role of transient secondary structure formation and dissociation in aS aggregation.
• To explore potential general mechanisms controlling IDP aggregation kinetics.

Main Methods:

• Utilized advanced biophysical techniques to study protein dynamics at sub-microsecond timescales.
• Analyzed the formation and dissociation kinetics of transient secondary structures in aS.
• Correlated secondary structure dynamics with tertiary structure rearrangements.

Main Results:

• Transient beta-sheets form rapidly (sub-microsecond) at positions relevant to aS amyloid fibrils.
• The kinetics of beta-sheet formation are outcompeted by rapid secondary structure dissociation rates.
• Dissociation times of secondary structures are comparable to tertiary structure rearrangement dynamics.

Conclusions:

• Fast secondary structure dissociation kinetics in aS limit the formation of stable beta-sheets, explaining low overall secondary structure content.
• These rapid dissociation kinetics may slow down conformational selection, acting as a general mechanism to control IDP aggregation.
• The findings provide insights into the aggregation pathways of intrinsically disordered proteins and potential therapeutic targets.