A simulated intermediate state for folding and aggregation provides insights into ΔN6 β2-microglobulin amyloidogenic...

Area of Science:

• Biochemistry
• Computational Biology
• Medical Biochemistry

Background:

• Dialysis-related amyloidosis (DRA) is characterized by amyloid plaques primarily composed of a cleaved variant of beta2-microglobulin (ΔN6).
• Understanding the amyloidogenic potential of ΔN6 is crucial for comprehending DRA pathogenesis.

Purpose of the Study:

• To computationally investigate the structural basis of ΔN6 amyloidogenicity.
• To elucidate the mechanism by which ΔN6 nucleates fibrillogenesis, particularly under conditions relevant to DRA patients.

Main Methods:

• Molecular simulations were employed to study the folding and aggregation properties of ΔN6.
• The study analyzed the conformational changes and dimerization interfaces of ΔN6 at various pH levels.

Main Results:

• ΔN6, unlike wild-type beta2-microglobulin, efficiently nucleates fibrillogenesis in vitro at physiological pH.
• Mild acidification, mimicking synovial fluid in DRA patients, enhances ΔN6 aggregation.
• Deletion of the N-terminal hexapeptide induces an aggregation-prone intermediate state with an unstructured strand A and a native-like core.
• Strand A acts as a 'sticky hook' promoting dimer assembly, with detachment maximized at pH 6.2.
• Specific residues (Tyr10, His13, Phe30, His84) were identified as critical 'hot spots' for ΔN6 amyloidogenesis.

Conclusions:

• The N-terminal truncation in ΔN6 is key to its enhanced amyloidogenicity.
• Acidic conditions significantly promote ΔN6 fibril formation, explaining its role in DRA.
• The structural insights gained provide a foundation for future therapeutic strategies targeting ΔN6 aggregation.