Journal
MOLECULAR CELL
Volume 69, Issue 3, Pages 465-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2017.12.022
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Funding
- NIGMS [R01GM118530, P20GM104937, T32GM007601]
- ALS Association [17-IIP-342]
- Judith & Jean Pape Adams Charitable Foundation
- NIMH [T32MH020068]
- U.S. Department of Energy (DOE), Office of Science, Basic Energy Sciences (BES), Division of Material Sciences and Engineering [DE-SC0013979]
- National Science Foundation (NSF) [TG-MCB120014]
- Office of Science of the U.S. Department of Energy [DE-AC02-05CH11231]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007601, P30GM122732, P20GM104937, R01GM118530] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [T32MH020068] Funding Source: NIH RePORTER
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hnRNPA2, a component of RNA-processing membraneless organelles, forms inclusions when mutated in a syndrome characterized by the degeneration of neurons (bearing features ofamyotrophic 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 lowcomplexity (LC) domain is compact and intrinsically disordered as amonomer, 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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