Intrinsically disordered regions that drive phase separation form a robustly distinct protein class

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Biology

Background:

• Protein phase separation drives the formation of membrane-less organelles, essential for cellular functions.
• Intrinsically disordered regions (IDRs) are critical for the phase separation of many proteins.

Purpose of the Study:

• To identify and characterize IDRs that drive protein phase separation.
• To improve the prediction of phase-separating IDRs (PS IDRs).

Main Methods:

• Curated datasets of folded, intrinsically disordered (ID), and phase-separating ID (PS ID) sequences.
• Examined amino acid property scales to distinguish between protein region classes.
• Optimized a predictor (ParSe) for PS IDRs, incorporating amino acid interactions.

Main Results:

• Identified robust differences in amino acid properties between folded, ID, and PS ID sequences.
• Demonstrated that multiple combinations of property scales can predict protein phase separation.
• Developed an improved predictor (ParSe) with enhanced accuracy for PS IDRs and mutations.

Conclusions:

• Multiple, redundant mechanisms contribute to phase separation driven by IDRs.
• Amino acid properties and interactions are key determinants of protein phase separation.
• Findings advance the understanding of IDR classification and the molecular basis of phase separation.