[Immunoglobulin-Like Domains Are the Key to Understanding Amyloid Aggregation].

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Medicine

Background:

• Protein aggregation is implicated in various diseases.
• Immunoglobulin-like (Ig) domains are common structural motifs in proteins.
• The formation of amyloid aggregates typically involves fibrillar structures and nucleation phases.

Purpose of the Study:

• To review modern concepts of protein aggregation mechanisms.
• To highlight the role of Ig domains in amyloid formation.
• To introduce a newly described pathway of amyloid aggregation.

Main Methods:

• Literature review focusing on protein aggregation mechanisms.
• Analysis of structural properties of amyloid aggregates.
• Investigation of binding characteristics with amyloid dyes (Thioflavin T and Congo red).

Main Results:

• Ig domains serve as platforms for amyloid aggregate formation.
• Muscle proteins titin and myosin-binding protein C form amorphous, not fibrillar, amyloid aggregates.
• These aggregates exhibit a cross-β structure without increased overall β-structure content and bind amyloid dyes.
• Amyloid formation in these proteins lacks a nucleation phase and allows partial disaggregation.

Conclusions:

• A novel pathway of amyloid protein aggregation, termed self-templating amorphous β-assembly (conformational conversion by a prion-like mechanism), is identified.
• This pathway is characteristic of multidomain proteins within the sarcomeric cytoskeleton.
• The findings challenge traditional models of amyloid formation and suggest new therapeutic targets.