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

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

Research output: Contribution to journalArticlepeer-review

251 Scopus citations

Abstract

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. The RNA-binding protein hnRNPA2 is mutated in disease and found in membraneless organelles, but the mechanistic details of phase separation are unknown. Using NMR, simulation, and microscopy, Ryan et al. show how molecular alterations and interactions, common to a large family of disease-associated hnRNPs, alter phase separation and aggregation.

Original languageEnglish (US)
Pages (from-to)465-479.e7
JournalMolecular cell
Volume69
Issue number3
DOIs
StatePublished - Feb 1 2018
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Keywords

  • RNP granule
  • amyotrophic lateral sclerosis
  • frontotemporal dementia
  • inclusion body myopathy
  • intrinsically disordered protein
  • liquid-liquid phase separation
  • molecular dynamics simulation
  • protein aggregation
  • protein interactions
  • solution NMR spectroscopy

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