Macromolecular crowding and protein aggregation: Friend, foe or contextual force?

Area of Science:

• Cellular Biology
• Biophysics
• Biochemistry

Background:

• Protein aggregation is crucial for cellular functions but also linked to diseases.
• A framework is lacking to predict aggregation outcomes (productive vs. pathological).
• Macromolecular crowding is an intrinsic cellular feature influencing protein behavior.

Purpose of the Study:

• To review how macromolecular crowding shapes protein aggregation outcomes.
• To provide a framework for understanding functional vs. pathological aggregation.
• To identify therapeutic strategies targeting crowding conditions.

Main Methods:

• Review of existing literature on macromolecular crowding and protein aggregation.
• Analysis of physicochemical parameters modulated by crowding (volume exclusion, electrostatics, viscosity, etc.).
• Examination of liquid-liquid phase separation in protein aggregation.

Main Results:

• Crowding is a context-dependent modulator, not a universal promoter or inhibitor.
• Crowding amplifies misfolding vulnerabilities in susceptible proteins.
• Crowding facilitates productive assembly in regulated systems.

Conclusions:

• A framework is proposed to interpret how crowding yields divergent aggregation outcomes.
• The intracellular milieu governs aggregation dynamics.
• Modulating crowding offers therapeutic potential for misfolding diseases.