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A Self-Consistent Molecular Mechanism of β2-Microglobulin Aggregation.

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Area of Science:

  • Biochemistry
  • Protein Misfolding Diseases
  • Biophysics

Background:

  • Dialysis-related amyloidosis (DRA) is linked to beta2-microglobulin (β2m) aggregation.
  • The exact aggregation mechanism of β2m, especially concerning variants and pH, remains debated.
  • Understanding β2m's behavior is crucial for managing DRA.

Purpose of the Study:

  • To elucidate the aggregation mechanism of wild-type (WT) and pathogenic β2m variants (V27M, D76N).
  • To investigate the influence of physiological and acidic pH on β2m aggregation.
  • To characterize both the initiation (monomeric) and termination (fibrillar) states of β2m aggregation.

Main Methods:

  • Utilized enhanced sampling approaches to characterize native monomeric and aggregated fibrillar states of β2m.
  • Analyzed the behavior of WT and pathogenic β2m variants at neutral and acidic pH.
  • Applied a propensity-stability approach to assess aggregation initiation and termination.

Main Results:

  • Pathogenic β2m mutants retain more native folds at neutral pH compared to WT.
  • At acidic pH, all variants show increased partially unfolded states, with varying extents (WT < V27M < D76N).
  • All variants exhibit pH-dependent protofilament separation and increased binding affinity at acidic pH, with relative order WT < V27M < D76N.

Conclusions:

  • β2m aggregation shifts from native-like to conformational switch-initiated fibrillation as pH decreases.
  • Both aggregation initiation (propensity) and termination (stability) play critical roles in the overall process.
  • The findings provide a mechanistic explanation for the heterogeneous behavior of β2m variants in DRA.