How does protein aggregate structure affect mechanisms of disaggregation?

Area of Science:

• Biochemistry
• Cell Biology
• Structural Biology

Background:

• Protein misfolding and aggregation are implicated in neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's.
• Cellular proteostasis networks, involving molecular chaperones, manage protein folding and prevent aggregation.
• Key knowledge gaps exist regarding the differential susceptibility of protein aggregates to chaperone-mediated disassembly.

Purpose of the Study:

• To investigate the factors influencing the disaggregation of structurally diverse protein aggregates by molecular chaperones.
• To elucidate the mechanistic basis for the varying efficacy of chaperone intervention in protein aggregation disorders.

Main Methods:

• Categorization of protein aggregates into amyloid fibrils and amorphous clusters based on structural properties.
• Analysis of aggregate characteristics, including size, internal structure, surface dynamics, and chaperone-binding site accessibility.
• Integration of single-molecule biophysics, structural biology, and computational modeling approaches.

Main Results:

• Amyloid fibrils exhibit ordered, cross-β-sheet structures and nucleation-driven growth.
• Amorphous aggregates arise from heterogeneous interactions of partially unfolded proteins, lacking ordered structure but possessing specific assembly constraints.
• Both amorphous and amyloid aggregation pathways can be interconnected, leading to co-occurrence of different aggregate types.

Conclusions:

• Molecular chaperone efficacy in remodeling and disassembling protein aggregates is contingent upon aggregate characteristics.
• The mechanistic complexity, heterogeneity, and dynamic nature of protein aggregates present significant challenges.
• Innovative, multidisciplinary approaches are essential to understand protein aggregation and disaggregation dynamics in cellular contexts.