TDP-43 multidomains and RNA modulate interactions and viscoelasticity in biomolecular condensates

Area of Science:

• Biochemistry
• Molecular Biology
• Biophysics

Background:

• RNA-binding proteins form biomolecular condensates via phase separation.
• Intrinsically disordered regions (IDRs) drive phase separation, but folded domains and RNA also play roles.
• Molecular mechanisms regulating condensate formation and properties are not fully understood.

Purpose of the Study:

• Investigate how TDP-43's multidomain structure (IDR, RRMs, NTD) interacts with RNA.
• Determine the effect of these interactions on phase separation characteristics.

Main Methods:

• Utilized molecular dynamics simulations.
• Analyzed interactions between TDP-43 domains and RNA.
• Assessed condensate packing, viscosity, and elasticity.

Main Results:

• IDR interactions are dominant in TDP-43 constructs.
• RRM2 increases condensate packing; NTD decreases it.
• RNA binding alters TDP-43 interactions, changing condensate viscoelasticity (RRMs increase viscosity, NTD decreases it; polyA increases elasticity).

Conclusions:

• TDP-43's multidomain structure and RNA interactions regulate condensate organization.
• These interactions modulate the viscoelastic properties of biomolecular condensates.
• Findings provide insights into the molecular basis of TDP-43 condensate behavior.