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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.

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Neuroscience Graduate Program, Brown University, Providence, RI 02912, USA.
Department of Chemical and Biomolecular Engineering, Lehigh University, Bethlehem, PA 18015, USA.
Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912, USA.
Graduate Program in Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912, USA.
Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912, USA. Electronic address:


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.


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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