List of publications for the week of November 8, 2021
Glycine-Rich Peptides from FUS Have an Intrinsic Ability to Self-Assemble into Fibers and Networked Fibrils
(2021) Biochemistry, .
Kar, M.a , Posey, A.E.b , Dar, F.c , Hyman, A.A.a , Pappu, R.V.b
a Max Planck Institute of Cell Biology and Genetics (MPI-CBG), Dresden, 01307, Germany
b Dept. of Biomedical Engineering and Center for Science and Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, MO 63130, United States
c Department of Physics, Washington University in St. Louis, St. Louis, MO 63130, United States
Glycine-rich regions feature prominently in intrinsically disordered regions (IDRs) of proteins that drive phase separation and the regulated formation of membraneless biomolecular condensates. Interestingly, the Gly-rich IDRs seldom feature poly-Gly tracts. The protein fused in sarcoma (FUS) is an exception. This protein includes two 10-residue poly-Gly tracts within the prion-like domain (PLD) and at the interface between the PLD and the RNA binding domain. Poly-Gly tracts are known to be highly insoluble, being potent drivers of self-assembly into solid-like fibrils. Given that the internal concentrations of FUS and FUS-like molecules cross the high micromolar and even millimolar range within condensates, we reasoned that the intrinsic insolubility of poly-Gly tracts might be germane to emergent fluid-to-solid transitions within condensates. To assess this possibility, we characterized the concentration-dependent self-assembly for three non-overlapping 25-residue Gly-rich peptides derived from FUS. Two of the three peptides feature 10-residue poly-Gly tracts. These peptides form either long fibrils based on twisted ribbon-like structures or self-supporting gels based on physical cross-links of fibrils. Conversely, the peptide with similar Gly contents but lacking a poly-Gly tract does not form fibrils or gels. Instead, it remains soluble across a wide range of concentrations. Our findings highlight the ability of poly-Gly tracts within IDRs that drive phase separation to undergo self-assembly. We propose that these tracts are likely to contribute to nucleation of fibrillar solids within dense condensates formed by FUS. © 2021 American Chemical Society.
National Institutes of HealthNIH5R01056114
Air Force Office of Scientific ResearchAFOSRFA9550-20-1-0241
Human Frontier Science ProgramHFSPRGP0034/2017
Document Type: Article
Publication Stage: Article in Press