Principles Governing the Phase Separation of Multidomain Proteins

Area of Science:

• Cell Biology
• Biochemistry
• Biophysics

Background:

• Membraneless organelles, or biological condensates, regulate crucial cellular processes like gene transcription and protein quality control.
• Liquid-liquid phase separation (LLPS) is a proposed mechanism for biological condensate formation, involving multivalent macromolecules.
• Multivalent interactions, encompassing both folded and disordered protein regions, drive LLPS and dictate condensate properties.

Purpose of the Study:

• To highlight the impact of domain architecture and interdomain interactions on the phase separation of multidomain protein condensates.
• To illustrate general principles of these interactions using examples of multidomain proteins involved in nucleic acid binding and protein quality control.
• To showcase how LLPS properties of folded and disordered regions can be utilized to engineer functional condensates.

Main Methods:

• Review of experimental and theoretical investigations on biological condensates and LLPS.
• Analysis of multidomain proteins with folded and disordered regions involved in cellular regulation.
• Discussion of strategies for engineering multidomain constructs for controlled condensate formation.

Main Results:

• Multidomain proteins are suitable macromolecules for promoting LLPS due to their multivalent interaction potential.
• The interplay between folded and disordered regions significantly influences the phase separation behavior of proteins.
• Engineered multidomain constructs can form condensates with tailored assembly and functional characteristics.

Conclusions:

• Domain architecture and interdomain interactions are critical determinants of multidomain protein phase separation.
• Leveraging LLPS properties of protein regions offers a route to designing functional biological condensates.
• Further development of computational models is needed to complement experimental studies for deeper insights into multidomain protein condensates.