A Simple Principle for Understanding the Combined Cellular Protein Folding and Aggregation

Area of Science:

• Biochemistry
• Molecular Biology
• Biophysics

Background:

• Protein folding and thermodynamic stability are traditionally considered key to preventing protein aggregation.
• However, cellular factors can inhibit aggregation irrespective of protein folding kinetics or stability, posing a challenge to existing models.

Purpose of the Study:

• To resolve the apparent contradiction between protein folding principles and the aggregation-inhibiting effects of cellular factors.
• To propose a unifying model that explains how protein aggregation is controlled.
• To highlight the role of intermolecular forces in preventing aggregation.

Main Methods:

• Conceptual model development based on distinguishing protein folding from aggregation.
• Analysis of intermolecular interactions, specifically repulsive forces.
• Correlation of repulsive force magnitude with molecular size and surface properties.

Main Results:

• Protein aggregation is controlled by intermolecular interactions, distinct from intramolecular interactions governing protein folding.
• Intermolecular repulsive forces, arising from factors like excluded volume and surface charges of cellular macromolecules, are crucial for preventing aggregation.
• These repulsive forces explain the generic chaperone activity of soluble macromolecules.

Conclusions:

• Protein aggregation is not solely a consequence of misfolding; it is governed by intermolecular forces.
• Cellular macromolecules, through their physical properties, generate repulsive forces that inhibit aggregation independently of protein folding.
• This principle provides a new framework for understanding cellular protein homeostasis and the prevention of amyloid fibril formation.