Acquired Disorder and Asymmetry in a Domain-Swapped Model for γ-Crystallin Aggregation

Area of Science:

• Biochemistry
• Structural Biology
• Protein Misfolding

Background:

• Protein misfolding and aggregation are implicated in numerous pathological conditions.
• Studying these processes is challenging due to their inherent disorder.
• Gamma S-crystallin (γS-crystallin) is a stable, monomeric protein often studied in relation to protein aggregation.

Purpose of the Study:

• To capture and characterize aggregation intermediates of γS-crystallin.
• To investigate novel oligomerization pathways under specific conditions.
• To understand structural mechanisms relevant to protein misfolding disorders.

Main Methods:

• Crystallization of γS-crystallin under mildly acidic and oxidizing conditions.
• Structural analysis of the resulting oligomeric intermediates.
• Characterization of domain-swapping and disulfide bond formation.

Main Results:

• Novel octameric structures were formed via strained domain-swapping and partial intermolecular disulfide bonds.
• The octamer consists of asymmetric tetramers, each containing twisted, domain-swapped dimers.
• Subunits within the tetramers exhibited varying degrees of acquired disorder, from local secondary structure loss to intrinsic disorder.

Conclusions:

• The identified octamer structure, stabilized by disulfide bonds, demonstrates a self-limited oligomerization mechanism.
• Disordered regions in the oligomers may act as seeds for further protein aggregation.
• These findings provide structural insights into protein aggregation relevant to cataract formation and other protein deposition diseases.