Journal
STRUCTURE
Volume 24, Issue 9, Pages 1537-1549Publisher
CELL PRESS
DOI: 10.1016/j.str.2016.07.007
Keywords
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Funding
- National Institute of General Medical Sciences (NIGMS) of the NIH [R01GM118530]
- Institutional Development Award (IDeA) from NIGMS [P20 GM104937]
- ALS Association [17-IIP-342]
- NIGMS training grant [T32 GM07601]
- 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-MCB-120014]
- Division of Biology and Medicine, Brown University
- NIGMS [P30GM103410, NCRR P30RR031153, P20RR018728, S10RR02763]
- National Science Foundation EPSCoR [0554548]
- U.S. Department of Energy (DOE) [DE-SC0013979] Funding Source: U.S. Department of Energy (DOE)
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RNA-binding protein TDP-43 mediates essential RNA processing but forms cytoplasmic neuronal inclusions via its C-terminal domain (CTD) in amyotrophic lateral sclerosis (ALS). It remains unclear if aggregated TDP-43 is neurotoxic and if similar to 50 ALS-associated missense mutations in TDP-43 CTD promote aggregation, or if loss of normal function plays a role in disease. Recent work points to the ability of related proteins to assemble into functional phase-separated ribonucleoprotein granules via their structurally disordered prion-like domains. Here, we provide atomic details on the structure and assembly of the low-complexity CTD of TDP-43 into liquid-liquid phase-separated in vitro granules and demonstrate that ALS-associated variants disrupt interactions within granules. Using nuclear magnetic resonance spectroscopy, simulation, and microscopy, we find that a subregion cooperatively but transiently folds into a helix that mediates TDP-43 phase separation. ALS-associated mutations disrupt phase separation by inhibiting interaction and helical stabilization. Therefore, ALS-associated mutations can disrupt TDP-43 interactions, affecting function beyond encouraging aggregation.
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