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Natural and Designed Proteins Inspired by Extremotolerant Organisms Can Form Condensates and Attenuate Apoptosis in Human Cells

  • Mike T. Veling
    Mike T. Veling
    Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
    Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts 02115, United States
  • Dan T. Nguyen
    Dan T. Nguyen
    Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
    Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts 02115, United States
  • Nicole N. Thadani
    Nicole N. Thadani
    Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
  • Michela E. Oster
    Michela E. Oster
    Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
    Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts 02115, United States
  • Nathan J. Rollins
    Nathan J. Rollins
    Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
    Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts 02115, United States
  • Kelly P. Brock
    Kelly P. Brock
    Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
  • Neville P. Bethel
    Neville P. Bethel
    Institute for Protein Design, University of Washington, Seattle, Washington 98195, United States
    Department of Biochemistry, University of Washington, Seattle, Washington 98195, United States
  • Samuel Lim
    Samuel Lim
    Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
    Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts 02115, United States
    More by Samuel Lim
  • David Baker
    David Baker
    Institute for Protein Design, University of Washington, Seattle, Washington 98195, United States
    Department of Biochemistry, University of Washington, Seattle, Washington 98195, United States
    Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, United States
    More by David Baker
  • Jeffrey C. Way
    Jeffrey C. Way
    Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
    Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts 02115, United States
  • Debora S. Marks
    Debora S. Marks
    Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
    Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, United States
  • Roger L. Chang*
    Roger L. Chang
    Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
    Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts 02115, United States
    Department of Systems & Computational Biology, Albert Einstein College of Medicine, Bronx, New York 10461, United States
    *Email: [email protected]
  • , and 
  • Pamela A. Silver*
    Pamela A. Silver
    Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
    Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts 02115, United States
    *Email: [email protected]
Cite this: ACS Synth. Biol. 2022, 11, 3, 1292–1302
Publication Date (Web):February 18, 2022
https://doi.org/10.1021/acssynbio.1c00572
Copyright © 2022 American Chemical Society

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    Abstract

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    Many organisms can survive extreme conditions and successfully recover to normal life. This extremotolerant behavior has been attributed in part to repetitive, amphipathic, and intrinsically disordered proteins that are upregulated in the protected state. Here, we assemble a library of approximately 300 naturally occurring and designed extremotolerance-associated proteins to assess their ability to protect human cells from chemically induced apoptosis. We show that several proteins from tardigrades, nematodes, and the Chinese giant salamander are apoptosis-protective. Notably, we identify a region of the human ApoE protein with similarity to extremotolerance-associated proteins that also protects against apoptosis. This region mirrors the phase separation behavior seen with such proteins, like the tardigrade protein CAHS2. Moreover, we identify a synthetic protein, DHR81, that shares this combination of elevated phase separation propensity and apoptosis protection. Finally, we demonstrate that driving protective proteins into the condensate state increases apoptosis protection, and highlights the ability of DHR81 condensates to sequester caspase-7. Taken together, this work draws a link between extremotolerance-associated proteins, condensate formation, and designing human cellular protection.

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acssynbio.1c00572.

    • Supplemental figures and table descriptions: Figures S1–S6 referenced in the main text, as well as full descriptions of the supplemental tables, which include an analysis of the disorder and repetitive distribution of the identified ExTol proteins, extended analysis of the relationship between the synthetic LEA proteins and apoptosis protection, additional data on the ApoE Western blotting and immunofluorescence experiments, data regarding our screen for condensate formation across the spectrum of apoptosis-related constructs, a broader look at condensate formation as it relates to apoptosis protection and condensate sequestration, and extended data on DHR81 (PDF)

    • Supplemental Methods including detailed information about the methodology used in this study (PDF)

    • Table S1 reporting sequences of all the proteins and designs discussed in this work (XLSX)

    • Table S2 reporting all normalized apoptosis data collected throughout this work (XLSX)

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    This article is cited by 4 publications.

    1. Nadiia Kasianchuk, Piotr Rzymski, Łukasz Kaczmarek. The biomedical potential of tardigrade proteins: A review. Biomedicine & Pharmacotherapy 2023, 158 , 114063. https://doi.org/10.1016/j.biopha.2022.114063
    2. Brett Janis, Michael A. Menze. Liquid–liquid phase in anhydrobiosis. 2023, 545-555. https://doi.org/10.1016/B978-0-12-823967-4.00017-8
    3. Zhi-Gang Qian, Sheng-Chen Huang, Xiao-Xia Xia. Synthetic protein condensates for cellular and metabolic engineering. Nature Chemical Biology 2022, 18 (12) , 1330-1340. https://doi.org/10.1038/s41589-022-01203-3
    4. Yuki Yoshida, Sae Tanaka. Deciphering the Biological Enigma—Genomic Evolution Underlying Anhydrobiosis in the Phylum Tardigrada and the Chironomid Polypedilum vanderplanki. Insects 2022, 13 (6) , 557. https://doi.org/10.3390/insects13060557

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