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Glycine-Rich Peptides from FUS Have an Intrinsic Ability to Self-Assemble into Fibers and Networked Fibrils

Published as part of the Biochemistry virtual special issue “Protein Condensates”

  • Mrityunjoy Kar
    Mrityunjoy Kar
    Max Planck Institute of Cell Biology and Genetics (MPI-CBG), 01307 Dresden, Germany
  • Ammon E. Posey
    Ammon E. Posey
    Department of Biomedical Engineering and Center for Science & Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, Missouri 63130, United States
  • Furqan Dar
    Furqan Dar
    Department of Physics, Washington University in St. Louis, St. Louis, Missouri 63130, United States
    More by Furqan Dar
  • Anthony A. Hyman*
    Anthony A. Hyman
    Max Planck Institute of Cell Biology and Genetics (MPI-CBG), 01307 Dresden, Germany
    *Email: [email protected]
  • , and 
  • Rohit V. Pappu*
    Rohit V. Pappu
    Department of Biomedical Engineering and Center for Science & Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, Missouri 63130, United States
    *Email: [email protected]
Cite this: Biochemistry 2021, 60, 43, 3213–3222
Publication Date (Web):October 14, 2021
https://doi.org/10.1021/acs.biochem.1c00501
Copyright © 2021 American Chemical Society

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    Abstract

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    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.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.biochem.1c00501.

    • Concentration dependence of CD spectra, TEM images of supramolecular assemblies, deconvolution of the FTIR spectra of lyophilized samples, violin plots of the occurrences of poly-Gly and poly-Ser tracts with one, two, and three interruptions in the tracts, and Tango2.0, (2) PASTA2.0, (3) and CamSol (4) predictions of aggregation propensities for peptides excised from human FUS (PDF)

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    Cited By

    This article is cited by 9 publications.

    1. Sergey Nazarov, Anass Chiki, Driss Boudeffa, Hilal A. Lashuel. Structural Basis of Huntingtin Fibril Polymorphism Revealed by Cryogenic Electron Microscopy of Exon 1 HTT Fibrils. Journal of the American Chemical Society 2022, 144 (24) , 10723-10735. https://doi.org/10.1021/jacs.2c00509
    2. Garrett M. Ginell, Alex S. Holehouse. An Introduction to the Stickers-and-Spacers Framework as Applied to Biomolecular Condensates. 2023, 95-116. https://doi.org/10.1007/978-1-0716-2663-4_4
    3. , Srivastav Ranganathan, Junlang Liu, Eugene Shakhnovich. Different states and the associated fates of biomolecular condensates. Essays in Biochemistry 2022, 66 (7) , 849-862. https://doi.org/10.1042/EBC20220054
    4. Henry R. Kilgore, Richard A. Young. Learning the chemical grammar of biomolecular condensates. Nature Chemical Biology 2022, 18 (12) , 1298-1306. https://doi.org/10.1038/s41589-022-01046-y
    5. Kristina Kastano, Pablo Mier, Zsuzsanna Dosztányi, Vasilis J. Promponas, Miguel A. Andrade-Navarro. Functional Tuning of Intrinsically Disordered Regions in Human Proteins by Composition Bias. Biomolecules 2022, 12 (10) , 1486. https://doi.org/10.3390/biom12101486
    6. Srivastav Ranganathan, Eugene Shakhnovich. The physics of liquid-to-solid transitions in multi-domain protein condensates. Biophysical Journal 2022, 121 (14) , 2751-2766. https://doi.org/10.1016/j.bpj.2022.06.013
    7. Alexander G. Kozlov, Xian Cheng, Hongshan Zhang, Min Kyung Shinn, Elizabeth Weiland, Binh Nguyen, Irina A. Shkel, Emily Zytkiewicz, Ilya J. Finkelstein, M. Thomas Record, Timothy M. Lohman. How Glutamate Promotes Liquid-liquid Phase Separation and DNA Binding Cooperativity of E. coli SSB Protein. Journal of Molecular Biology 2022, 434 (9) , 167562. https://doi.org/10.1016/j.jmb.2022.167562
    8. Mariana J. Amaral, Maria Heloisa O. Freire, Marcius S. Almeida, Anderson S. Pinheiro, Yraima Cordeiro. Phase separation of the mammalian prion protein: Physiological and pathological perspectives. Journal of Neurochemistry 2022, 584 https://doi.org/10.1111/jnc.15586
    9. Megan C. Cohan, Min Kyung Shinn, Jared M. Lalmansingh, Rohit V. Pappu. Uncovering Non-random Binary Patterns Within Sequences of Intrinsically Disordered Proteins. Journal of Molecular Biology 2022, 434 (2) , 167373. https://doi.org/10.1016/j.jmb.2021.167373

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