Beta turn propensity and a model polymer scaling exponent identify intrinsically disordered phase-separating proteins

Area of Science:

• Biochemistry and Molecular Biology
• Cell Biology
• Protein Biophysics

Background:

• Cellular processes rely on the controlled phase separation of biomolecules, often involving intrinsically disordered (ID) proteins.
• Protein phase separation is influenced by the balance between protein-protein and protein-solvent interactions.
• The hydrodynamic size of monomeric proteins, quantified by the polymer scaling exponent (v), reflects a similar interaction balance.

Purpose of the Study:

• To test the hypothesis that proteins with a higher propensity for phase separation exhibit a smaller mean polymer scaling exponent (v).
• To investigate the role of protein structure, specifically beta-turns, in the phase separation of intrinsically disordered proteins.
• To develop a predictive model for identifying phase-separating protein regions based on sequence characteristics.

Main Methods:

• Analysis of protein databases categorizing proteins as folded, disordered, or phase-separating disordered.
• Calculation of the polymer scaling exponent (v) and beta-turn propensity from protein sequences.
• Development and validation of a new algorithm, ParSe (partition sequence), for predicting phase-separating regions.

Main Results:

• Phase-separating disordered proteins showed significantly lower calculated mean values of v compared to non-phase-separating disordered proteins.
• A higher sequence-predicted propensity for beta-turns was observed in phase-separating disordered proteins.
• The ParSe algorithm accurately distinguished between folded, disordered, and phase-separating protein regions using sequence data.

Conclusions:

• Lower hydrodynamic size (v) and increased beta-turn propensity are characteristic of intrinsically disordered proteins that undergo phase separation.
• Beta-turns may act as nucleation sites by reducing desolvation penalties and facilitating favorable interactions within phase-separating regions.
• Combining v and beta-turn propensity offers a means to differentiate protein types and predict phase separation potential from primary sequences.