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Mol Cell. 2018 Feb 1;69(3):465-479.e7. doi: 10.1016/j.molcel.2017.12.022. Epub 2018 Jan 18.

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

Author information

1
Neuroscience Graduate Program, Brown University, Providence, RI 02912, USA.
2
Department of Chemical and Biomolecular Engineering, Lehigh University, Bethlehem, PA 18015, USA.
3
Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912, USA.
4
Graduate Program in Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912, USA.
5
Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912, USA. Electronic address: nicolas_fawzi@brown.edu.

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.

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

PMID:
29358076
PMCID:
PMC5801700
DOI:
10.1016/j.molcel.2017.12.022
[Indexed for MEDLINE]
Free PMC Article

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