Direct cryo-EM visualization of the β-sheet structure in curved amyloid protofibril

Area of Science:

• Biochemistry
• Structural Biology
• Biophysics

Background:

• Amyloid-related diseases are linked to protein misfolding and aggregation.
• Protofibrils are critical intermediates in amyloid formation but their structure is poorly understood.
• Understanding protofibril structure is key for developing effective therapeutic strategies.

Purpose of the Study:

• To directly visualize the intermolecular beta-sheet structure of amyloid protofibrils.
• To propose a structural model for amyloid protofibrils.
• To establish a framework for designing targeted diagnostic and therapeutic agents.

Main Methods:

• Cryo-electron microscopy was used for high-resolution imaging.
• Analysis of protofibrils formed by an insulin-derived peptide.
• Image processing to resolve structural features at the Ångstrom level.

Main Results:

• Direct visualization of amyloid protofibril structure revealed regularly spaced lines (4.7 Å) at their centers, indicative of beta-sheet structure.
• A model was proposed with a central beta-sheet core and surrounding random coiled regions.
• The protofibril structure differs from mature amyloid fibrils, explaining their distinct morphology.

Conclusions:

• Cryo-electron microscopy is effective for visualizing flexible structures like protofibrils.
• The partial beta-sheet formation in protofibrils contributes to their characteristic appearance.
• This study provides a conceptual basis for targeting protofibril structures in disease treatment.