Mechanistic View of hnRNPA2 Low-Complexity Domain Structure, Interactions, and Phase Separation Altered by Mutation and Arginine Methylation

作者：Ryan Veronica H; Dignon Gregory L; Zerze Gul H; Chabata Charlene V; Silva Rute; Conicella Alexander E; Amaya Joshua; Burke Kathleen A; Mittal Jeetain; Fawzi Nicolas L^*

来源：Molecular Cell, 2018, 69(3): 465-+.

DOI：10.1016/j.molcel.2017.12.022

hnRNPA2, a component of RNA-processing membraneless organelles, forms inclusions when mutated in a syndrome characterized by the degeneration of neurons (bearing features ofamyotrophic 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 lowcomplexity (LC) domain is compact and intrinsically disordered as amonomer, 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.

• 出版日期2018-2-1