Mechanistic View of hnRNPA2 Low-Complexity Domain Structure, Interactions, and Phase Separation Altered by Mutation and Arginine Methylation. Academic Article uri icon


  • hnRNPA2, a component of RNA-processing membraneless organelles, forms inclusions when mutated in a syndrome characterized by the degeneration of neurons (bearing features of amyotrophic lateral sclerosis [ALS] and frontotemporal dementia), muscle, and bone. Here we provide a unified structural view of hnRNPA2 self-assembly, aggregation, and interaction and the distinct effects of small chemical changes-disease mutations and arginine methylation-on these assemblies. The hnRNPA2 low-complexity (LC) domain is compact and intrinsically disordered as a monomer, retaining predominant disorder in a liquid-liquid phase-separated form. Disease mutations D290V and P298L induce aggregation by enhancing and extending, respectively, the aggregation-prone region. Co-aggregating in disease inclusions, hnRNPA2 LC directly interacts with and induces phase separation of TDP-43. Conversely, arginine methylation reduces hnRNPA2 phase separation, disrupting arginine-mediated contacts. These results highlight the mechanistic role of specific LC domain interactions and modifications conserved across many hnRNP family members but altered by aggregation-causing pathological mutations.

published proceedings

  • Mol Cell

altmetric score

  • 106.146

author list (cited authors)

  • Ryan, V. H., Dignon, G. L., Zerze, G. H., Chabata, C. V., Silva, R., Conicella, A. E., ... Fawzi, N. L.

citation count

  • 228

complete list of authors

  • Ryan, Veronica H||Dignon, Gregory L||Zerze, Gül H||Chabata, Charlene V||Silva, Rute||Conicella, Alexander E||Amaya, Joshua||Burke, Kathleen A||Mittal, Jeetain||Fawzi, Nicolas L

publication date

  • February 2018