Delicate balance between functionally required flexibility and aggregation risk in a β-rich protein

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Biophysics

Background:

• Protein aggregation is a general property driven by hydrophobic interactions.
• This process is implicated in severe diseases, but the mechanisms remain unclear.
• Understanding protein misfolding requires studying the interplay between folding, dynamics, and aggregation.

Purpose of the Study:

• To investigate the relationship between protein folding, breathing, function, and aggregation propensity.
• To identify dynamic species that lead to protein aggregation.
• To use cellular retinoic acid-binding protein 1 (CRABP1) as a model system.

Main Methods:

• Utilized a predominantly β-sheet protein (CRABP1) with well-characterized folding.
• Analyzed inherent structural fluctuations and dynamic species.
• Investigated the exposure of hydrophobic residues during protein opening.

Main Results:

• Identified near-native dynamic species that initiate aggregation.
• Demonstrated that protein breathing, specifically opening of the ligand-entry portal in CRABP1, exposes aggregation-prone hydrophobic sequences.
• Proposed that cellular concentrations of open CRABP1 conformations are below aggregation thresholds.

Conclusions:

• Protein function and conformational variability are delicately balanced against aggregation vulnerability.
• Protein aggregation is an inherent, yet controllable, risk associated with the evolution of protein folding and function.
• Nature fine-tunes protein dynamics to balance function and prevent aggregation under physiological conditions.