Determinants of Disordered Protein Co-Assembly Into Discrete Condensed Phases.

Area of Science:

• Cell biology
• Biophysics
• Molecular biology

Background:

• Cells contain membraneless compartments crucial for biochemical processes.
• These compartments, rich in protein and RNA, are formed via liquid-liquid phase separation (LLPS).
• Intrinsically disordered regions (IDRs) are common in proteins within these organelles, but their role in phase separation specificity is unclear.

Approach:

• Identified two intrinsically disordered regions (IDRs) that form distinct cellular condensates.
• Reconstituted model proteins in vitro to assess phase separation behavior.
• Utilized computational modeling and mutagenesis to analyze amino acid interactions and governing properties.

Key Points:

• Specific IDR sequences can independently drive the formation of distinct condensed phases.
• In vitro experiments confirmed that these model proteins do not co-partition, indicating sequence-encoded specificity.
• Identified key amino acids and chain properties responsible for homotypic and heterotypic interactions.

Conclusions:

• Condensation specificity is directly encoded within polypeptide sequences of IDRs.
• Physicochemical principles governing IDR interactions can direct subcellular organization.
• Discovered an 'IDR code' for constructing orthogonal membraneless compartments.