Beyond Misfolding: A New Paradigm for the Relationship Between Protein Folding and Aggregation

Area of Science:

• Biochemistry
• Molecular Biology
• Protein Science

Background:

• Protein aggregation is closely linked to protein folding, traditionally viewed as a sequential process.
• The conventional paradigm is incomplete, failing to explain how factors independent of folding influence aggregation.
• Inconsistencies between folding and aggregation necessitate a new theoretical framework.

Purpose of the Study:

• To propose a new framework for understanding the relationship between protein folding and aggregation.
• To explain how intrinsic and extrinsic factors independently regulate these processes.
• To provide a more comprehensive view of protein aggregation in the cellular environment.

Main Methods:

• Application of the universal principle of mutually independent intramolecular and intermolecular reaction rates.
• Analysis of how intrinsic and extrinsic factors independently affect rate constants.
• Development of a new theoretical model integrating folding and aggregation.

Main Results:

• Protein folding and aggregation are identified as two independent yet interconnected processes.
• The new framework elucidates the roles of charges and cellular macromolecules in preventing aggregation.
• Insights are provided into molecular chaperones, proteome solubility, and proteinopathies.

Conclusions:

• A paradigm shift is proposed, treating folding and aggregation as independent processes.
• This framework offers a more complete understanding of protein misfolding and aggregation.
• It refines current knowledge on cellular mechanisms maintaining proteome solubility and preventing disease.