Physical basis of amyloid fibril polymorphism

Area of Science:

• Structural biology
• Biophysics
• Biochemistry

Background:

• Amyloid fibril polymorphism presents a significant challenge in understanding disease mechanisms.
• The structural basis for variations in amyloid fibril morphology remains poorly understood.

Purpose of the Study:

• To investigate the structural basis of polymorphism in amyloid fibrils formed by an immunoglobulin light chain peptide fragment.
• To establish a framework for rationalizing and predicting cross-β fibril structures and their polymorphism.

Main Methods:

• Electron cryomicroscopy (cryo-EM) was employed to reconstruct fibril structures.
• Analysis of fibril morphologies based on the arrangement of conserved building blocks.

Main Results:

• Observed fibril morphologies differ in the number and arrangement of a conserved structural building block.
• The spectrum of observed morphologies is dictated by competing forces, including beta-sheet twist and peptide-peptide interactions.
• A limited set of physical parameters controls the diverse fibril architectures.

Conclusions:

• A framework is provided for understanding and predicting the structure and polymorphism of cross-β fibrils.
• Physical parameters, particularly beta-sheet twist and inter-peptide forces, are key determinants of amyloid fibril architecture.