Disease-relevant β₂-microglobulin variants share a common amyloid fold.

Area of Science:

• Biochemistry
• Structural Biology
• Medical Research

Background:

• Beta-2 microglobulin (β2m) and its truncated form ΔΝ6 are implicated in dialysis-related amyloidosis (DRA).
• Specific point mutations in β2m lead to distinct amyloidosis pathologies, affecting different organs.
• Understanding the structural basis of these fibril formations is crucial for disease mechanism elucidation.

Purpose of the Study:

• To determine the in vitro structures of amyloid fibrils formed by β2m variants.
• To investigate the structural basis for the distinct pathologies caused by β2m mutations.
• To explore the assembly principles of β2m amyloid fibrils.

Main Methods:

• Cryo-electron microscopy (cryoEM) was used to analyze fibril structures.
• Fibrils were formed from β2m variants under identical in vitro conditions.
• Structural analysis focused on identifying common building blocks and polymorphic arrangements.

Main Results:

• Each β2m variant formed polymorphic amyloid fibrils.
• A common 'lego-like' amyloid building block was identified across different variant fibril structures.
• The structural diversity arises from the assembly of this common building block.

Conclusions:

• The study proposes a 'many sequences, one amyloid fold' paradigm for β2m amyloid formation.
• This contrasts with the 'one sequence, many amyloid folds' model observed in intrinsically disordered proteins.
• The findings provide insights into the structural mechanisms underlying different β2m-associated amyloidosis diseases.