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Cell. 2017 Oct 19;171(3):615-627.e16. doi: 10.1016/j.cell.2017.08.048. Epub 2017 Sep 21.

Structure of FUS Protein Fibrils and Its Relevance to Self-Assembly and Phase Separation of Low-Complexity Domains.

Author information

1
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520, USA; Postdoctoral Research Associate Program, National Institute of General Medical Sciences, National Institutes of Health, Bethesda, MD 20892-6200, USA.
2
Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA.
3
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520, USA.
4
National High Magnetic Field Laboratory, Florida State University, Tallahassee, FL 32310, USA.
5
Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA. Electronic address: steven.mcknight@utsouthwestern.edu.
6
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520, USA. Electronic address: robertty@mail.nih.gov.

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.

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

Comment in

PMID:
28942918
PMCID:
PMC5650524
DOI:
10.1016/j.cell.2017.08.048
[Indexed for MEDLINE]
Free PMC Article

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