Excitation Energy Migration Unveils Fuzzy Interfaces within the Amyloid Architecture

Area of Science:

• Biophysics
• Structural Biology
• Biochemistry

Background:

• Amyloid fibrils, characterized by a cross-β amyloid core, are implicated in severe human diseases.
• Understanding the supramolecular architecture of amyloid fibrils is crucial for disease mechanism studies.
• The role of transient interactions in disordered protein segments remains poorly understood.

Observation:

• A novel application of interchain excitation energy migration via homo-Förster resonance energy transfer (homo-FRET) was employed.
• Site-specific homo-FRET efficiencies were measured using fluorescence depolarization.
• This allowed for the construction of a 2D proximity correlation map of α-synuclein within fibrils.

Findings:

• The study successfully deciphered the architecture of human α-synuclein amyloid fibrils.
• A detailed map of supramolecular packing within the fibrils was generated.
• Unique heteroterminal cross-talks at the fuzzy interprotofilament interfaces of parallel-in-register amyloid spines were identified.

Implications:

• This research provides a method to study the role of protein disorder in amyloid formation.
• The findings can help differentiate between amyloid polymorphs and their associated disease phenotypes.
• Applications include understanding the broader impact of protein disorder on amyloid structure and disease.