Determinants that enable disordered protein assembly into discrete condensed phases.

Area of Science:

• Cell biology
• Biochemistry
• Biophysics

Background:

• Cells contain numerous membraneless compartments crucial for biochemical processes.
• These compartments, rich in proteins and RNA, form via liquid-liquid phase separation.
• Intrinsically disordered regions (IDRs) are common in proteins within these organelles.

Purpose of the Study:

• To investigate if intrinsically disordered region (IDR) sequences alone can determine the formation of distinct condensed phases.
• To understand the physicochemical principles governing the selective condensation of IDRs.

Main Methods:

• Expressing pairs of IDRs in cells to observe condensate formation.
• Reconstituting model proteins with IDRs in vitro to assess co-partitioning.
• Utilizing computational modeling and mutagenesis to identify key amino acids and chain properties.

Main Results:

• Identified a pair of IDRs that form spatially distinct condensates in cells.
• Demonstrated that these IDRs do not co-partition in vitro, indicating sequence-specific condensation.
• Uncovered specific amino acids and chain properties that govern homotypic and heterotypic interactions for selective condensation.

Conclusions:

• The sequence of intrinsically disordered regions (IDRs) directly encodes specificity for forming distinct membraneless compartments.
• Physicochemical principles derived from IDR sequences can guide subcellular organization.
• An 'IDR code' can be utilized to engineer orthogonal membraneless compartments.