Programming molecular self-assembly of intrinsically disordered proteins containing sequences of low complexity

Area of Science:

• Cell Biology
• Biomolecular Engineering
• Protein Science

Background:

• Intrinsically disordered proteins (IDPs) with low-complexity sequences (SLCs) form dynamic, phase-separated intracellular structures.
• These structures are crucial for cellular functions like signaling, compartmentalization, and stabilization.
• Current understanding and modeling capabilities for these complex assemblies are limited.

Purpose of the Study:

• To establish design principles for intrinsically disordered proteins (IDPs) that undergo phase separation.
• To enable the rational design of diverse, multicomponent protein-rich assemblies.
• To explore the relationship between genetic encoding, molecular properties, and macroscale assembly behavior.

Main Methods:

• Theoretical analysis of archetypal IDP sequences to interpret phase behavior.
• Development of design rules for IDPs with specific low-complexity sequences (SLCs).
• Creation of a large library of multicomponent protein-rich structures through rational design.

Main Results:

• Demonstrated successful design of IDPs that phase separate into diverse assemblies.
• Generated protein-rich structures ranging from uniform puncta to multilayered granular assemblies.
• Showcased the ability to predict and program the formation of specific IDP-rich structures.

Conclusions:

• Predictable and programmable design of IDP-rich assemblies is achievable.
• Provides insights into genetic-to-macroscale relationships governing hierarchical IDP assemblies.
• Offers a foundation for molecular-level engineering of self-assembled, recombinant IDP-rich materials.