Matrin-3 forms spherical and wormlike assemblies that are modulated by RNA binding and ALS/FTD-associated mutations

Area of Science:

• Biochemistry
• Molecular Biology
• Neuroscience

Background:

• Matrin-3 (MATR3) is an RNA-binding protein (RBP) implicated in familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
• MATR3 possesses distinct structural domains, including RNA recognition motifs, zinc-finger motifs, and intrinsically disordered regions.

Purpose of the Study:

• To investigate the self-assembly characteristics of human MATR3 at the nanoscale.
• To elucidate the structural basis for MATR3's assembly behavior and its modulation by RNA and disease-associated mutations.

Main Methods:

• Utilized computational modeling and experimental techniques to study MATR3 assembly.
• Analyzed concentration-dependent transitions from spherical to wormlike assemblies.
• Investigated the impact of RNA binding and ALS/FTD mutations on MATR3 assemblies.

Main Results:

• Human MATR3 forms nanoscale spherical assemblies (20-30 nm) at low concentrations, transitioning to wormlike structures at higher concentrations.
• MATR3 exhibits an inverse bolaamphiphile-like architecture, explaining its concentration-dependent assembly.
• RNA binding shortens MATR3 wormlike assemblies, while ALS/FTD mutations reduce RNA's modulatory effect.

Conclusions:

• MATR3 self-assembly is concentration-dependent and structurally driven, resembling amphiphilic molecule behavior.
• RNA interactions and ALS/FTD mutations significantly alter MATR3 assembly dynamics.
• Findings provide insights into the molecular mechanisms underlying MATR3-associated neurodegenerative diseases.