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

Topic: Brain proteins, microglia and lab models

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.

@article{ryan2018-29358076,
  author  = {Ryan, V. H. and Dignon, G. L. and Zerze, G. H. and Chabata, C. V. and Silva, R. and Conicella, A. E. and Amaya, J. and Burke, K. A. and others},
  title   = {{Mechanistic View of hnRNPA2 Low-Complexity Domain Structure, Interactions, and Phase Separation Altered by Mutation and Arginine Methylation}},
  journal = {Molecular cell},
  year    = {2018},
  doi     = {10.1016/j.molcel.2017.12.022},
  pmid    = {29358076},
  url     = {https://doi.org/10.1016/j.molcel.2017.12.022}
}

Key findings

• 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.

Why it matters

This laboratory work describes how the hnRNPA2 protein's low-complexity domain assembles and aggregates, and how disease-causing mutations and arginine methylation change these assemblies. It is basic mechanistic research and does not test any treatment, prevention or cure in people.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1016/j.molcel.2017.12.022
• PubMed: 29358076
• Original source →
• Free full text: Molecular Cell →

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Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

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Later studies that cite this one

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• Cytoplasmic TDP-43 De-mixing Independent of Stress Granules Drives Inhibition of Nuclear Import, Loss of Nuclear TDP-43, and Cell Death Neuron · 2019-03-07 · usefulness score 56/100 · Lewy body dementia
• Phase Separation of FUS Is Suppressed by Its Nuclear Import Receptor and Arginine Methylation Cell · 2018-04-01 · usefulness score 54/100 · Lewy body dementia
• Poly(ADP-Ribose) Prevents Pathological Phase Separation of TDP-43 by Promoting Liquid Demixing and Stress Granule Localization Molecular cell · 2018-08-09 · usefulness score 53/100 · Lewy body dementia
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• PARylation regulates stress granule dynamics, phase separation, and neurotoxicity of disease-related RNA-binding proteins Cell research · 2019-02-06 · usefulness score 49/100 · Brain tissue and pathology

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