2025
Molecular Cell

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

Authors:

Macy L. Sprunger, Min Kyung Shinn, Sabrina K. Talir, Ken Lee, Rohit V. Pappu, Meredith E. Jackrel

Keywords:

Matrin-3; TDP-43; amyotrophic lateral sclerosis; ALS; RNA-binding protein; RBP; intrinsically disordered proteins; biomolecular condensates; phase separation

Abstract:

Matrin-3 (MATR3) is an RNA-binding protein (RBP) that is associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). MATR3 features two RNA recognition motifs, two zinc-finger motifs, and four intrinsically disordered regions. Here, we report that human MATR3 associates with itself to form nanoscale spherical assemblies at ultralow protein concentrations. Through concentration-dependent associations, the spheres, which are 20–30 nm in diameter, transition into wormlike assemblies. These observations are reminiscent of sphere-to-worm transitions and micellization of amphiphilic molecules. Using computations and experiments, we discovered that the pattern of inter-domain attractions and repulsions gives MATR3 an inverse bolaamphiphile-like architecture that explains the concentration-dependent assembly characteristics. RNA binding causes shortening of wormlike assemblies of MATR3, whereas ALS/FTD-associated mutations render MATR3 assemblies less responsive to modulation by RNA. Overall, our findings highlight the unique assemblies formed by MATR3 while also showing how RNA-dependent interactions and ALS/FTD-associated mutations modulate the assemblies.