Different Folding States from the Same Protein Sequence Determine Reversible vs Irreversible Amyloid Fate

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Biology

Background:

• Amyloid fibrils, characterized by a cross-β structure, are formed by protein self-assembly.
• Amyloid-related diseases are prevalent and currently incurable due to the stability of these fibrils.
• The possibility of labile (reversible) amyloids is linked to proteins with low-complexity domains, but the mechanism is poorly understood.

Purpose of the Study:

• To investigate whether globular proteins can form both reversible and irreversible amyloid fibrils.
• To understand the role of protein folding pathways in amyloid lability and reversibility.
• To elucidate the structural differences between reversible and irreversible amyloid fibrils.

Main Methods:

• Utilized human lysozyme and hen egg white lysozyme.
• Induced self-assembly into amyloid fibrils via different folding pathways.
• Characterized fibril structure at molecular and mesoscopic levels, including cross-β architecture and polymorphism.

Main Results:

• Demonstrated that the same protein sequence can yield both reversible and irreversible amyloid fibrils based on the folding path.
• Confirmed the cross-β structure in both fibril types but identified distinct fibril core structures and β-sheet arrangements.
• Observed significant differences in mesoscopic polymorphism and lability between the two amyloid states.

Conclusions:

• Protein folding pathways are critical determinants of amyloid fibril lability and reversibility.
• A mechanistic link exists between protein folding states and the reversible/irreversible nature of amyloids.
• This finding challenges the notion that protein sequence alone dictates amyloid stability and offers new perspectives for therapeutic strategies.