@article{72250d82143e4c6dbb64d9835578f399,
title = "Structure of FUS Protein Fibrils and Its Relevance to Self-Assembly and Phase Separation of Low-Complexity Domains",
abstract = "Polymerization and phase separation of proteins containing low-complexity (LC) domains are important factors in gene expression, mRNA processing and trafficking, and localization of translation. We have used solid-state nuclear magnetic resonance methods to characterize the molecular structure of self-assembling fibrils formed by the LC domain of the fused in sarcoma (FUS) RNA-binding protein. From the 214-residue LC domain of FUS (FUS-LC), a segment of only 57 residues forms the fibril core, while other segments remain dynamically disordered. Unlike pathogenic amyloid fibrils, FUS-LC fibrils lack hydrophobic interactions within the core and are not polymorphic at the molecular structural level. Phosphorylation of core-forming residues by DNA-dependent protein kinase blocks binding of soluble FUS-LC to FUS-LC hydrogels and dissolves phase-separated, liquid-like FUS-LC droplets. These studies offer a structural basis for understanding LC domain self-assembly, phase separation, and regulation by post-translational modification. Solid-state NMR of FUS fibrils provides structural insight into phase separation of low-complexity domains and its regulation by post-translational modification.",
keywords = "FUS, amyloid structure, amyotrophic lateral sclerosis, electron microscopy, labile cross-β polymer, liquid droplet, liquid-liquid phase separation, low-complexity sequence, neurodegeneration, solid-state nuclear magnetic resonance",
author = "Murray, {Dylan T.} and Masato Kato and Yi Lin and Thurber, {Kent R.} and Ivan Hung and McKnight, {Steven L.} and Robert Tycko",
note = "Funding Information: We thank Drs. Matthew Pratt at University of Southern California and Tom Muir at Princeton University for providing AvaDnaE intein constructs. We thank Yonghao Yu and Leeju Wu for technical assistance. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. D.T.M. was supported by a Postdoctoral Research Associate (PRAT) fellowship from the National Institute of General Medical Sciences (NIGMS), award number 1Fi2GM117604-01. Structure and assignment calculations and molecular dynamics simulations used the high-performance computing resources of the NIH Biowulf cluster. Solid-state NMR data at 21.1 T were acquired under project P08483 through the Users Program of NHMFL, which is supported by NSF DMR-1157490 and the State of Florida. We thank Dr. Charles D. Schwieters for assistance with structure calculations. Work performed at UTSWMC was supported by grant 5U01GM107623-03 from the NIGMS and unrestricted funds provided to S.L.M. by an anonymous donor. Funding Information: We thank Drs. Matthew Pratt at University of Southern California and Tom Muir at Princeton University for providing AvaDnaE intein constructs. We thank Yonghao Yu and Leeju Wu for technical assistance. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health . D.T.M. was supported by a Postdoctoral Research Associate (PRAT) fellowship from the National Institute of General Medical Sciences (NIGMS), award number 1Fi2GM117604-01 . Structure and assignment calculations and molecular dynamics simulations used the high-performance computing resources of the NIH Biowulf cluster. Solid-state NMR data at 21.1 T were acquired under project P08483 through the Users Program of NHMFL, which is supported by NSF DMR-1157490 and the State of Florida . We thank Dr. Charles D. Schwieters for assistance with structure calculations. Work performed at UTSWMC was supported by grant 5U01GM107623-03 from the NIGMS and unrestricted funds provided to S.L.M. by an anonymous donor. Publisher Copyright: {\textcopyright} 2017",
year = "2017",
month = oct,
day = "19",
doi = "10.1016/j.cell.2017.08.048",
language = "English (US)",
volume = "171",
pages = "615--627.e16",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",
}