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

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

doi:10.1016/j.molcel.2017.12.022

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

Journal Article · Thu Jan 18 00:00:00 EST 2018 · Molecular Cell

DOI:https://doi.org/10.1016/j.molcel.2017.12.022· OSTI ID:1548831

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

hnRNPA2, a component of RNA-processing membraneless organelles, forms inclusions when mutatedin a syndrome characterized by the degeneration of neurons (bearing features of amyotrophic lateral sclerosis [ALS] and frontotemporal dementia), muscle,and bone. In this work 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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)

Sponsoring Organization:: ALS Association; Brown Institute for Brain Science; Judith & Jean Pape Adams Charitable Foundation; National Institute of General Medical Sciences (NIGMS); National Institute of Mental Health (NIMH); National Science Foundation (NSF); USDOE Office of Science (SC), Advanced Scientific Computing Research (ASCR); USDOE Office of Science (SC), Basic Energy Sciences (BES). Materials Sciences & Engineering Division

Grant/Contract Number:: AC02-05CH11231; SC0013979

OSTI ID:: 1548831

Alternate ID(s):: OSTI ID: 1463871

Journal Information:: Molecular Cell, Journal Name: Molecular Cell Journal Issue: 3 Vol. 69; ISSN 1097-2765

Publisher:: Cell Press - ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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

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