The structure of a β₂-microglobulin fibril suggests a molecular basis for its amyloid polymorphism

Area of Science:

• Biochemistry
• Structural Biology
• Biophysics

Background:

• Amyloid fibrils, characterized by a cross-β fold, are implicated in various diseases.
• The structural variations of amyloid fibrils formed from different proteins are not fully understood.
• Beta2-microglobulin (β2m) is the protein responsible for dialysis-related amyloidosis.

Purpose of the Study:

• To elucidate the structure of amyloid fibrils formed in vitro from β2-microglobulin (β2m).
• To compare the structural features of β2m amyloid fibrils with those from other amyloid diseases.
• To understand the mechanisms underlying amyloid fibril formation.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to determine fibril architecture.
• Magic-angle spinning nuclear magnetic resonance (MAS-NMR) provided atomic-level structural details.
• In vitro fibril formation assays were conducted.

Main Results:

• A detailed structure of a β2m amyloid fibril was determined, composed of two protofilaments.
• The β2m subunits in the fibril adopted a fold distinct from its native state but shared β-strand similarities with other amyloids.
• Unique features included perpendicular π-stacking interactions and a stabilizing intramolecular disulfide bond.
• A second fibril morphology was modeled, sharing the same subunit fold.

Conclusions:

• The study reveals specific structural characteristics of β2m amyloid fibrils.
• It highlights both conserved and unique structural motifs across different amyloid types.
• Findings contribute to understanding the diversity of amyloid structures and formation pathways.