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IDPology of the living cell: intrinsic disorder in the subcellular compartments of the human cell

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Abstract

Intrinsic disorder can be found in all proteomes of all kingdoms of life and in viruses, being particularly prevalent in the eukaryotes. We conduct a comprehensive analysis of the intrinsic disorder in the human proteins while mapping them into 24 compartments of the human cell. In agreement with previous studies, we show that human proteins are significantly enriched in disorder relative to a generic protein set that represents the protein universe. In fact, the fraction of proteins with long disordered regions and the average protein-level disorder content in the human proteome are about 3 times higher than in the protein universe. Furthermore, levels of intrinsic disorder in the majority of human subcellular compartments significantly exceed the average disorder content in the protein universe. Relative to the overall amount of disorder in the human proteome, proteins localized in the nucleus and cytoskeleton have significantly increased amounts of disorder, measured by both high disorder content and presence of multiple long intrinsically disordered regions. We empirically demonstrate that, on average, human proteins are assigned to 2.3 subcellular compartments, with proteins localized to few subcellular compartments being more disordered than the proteins that are localized to many compartments. Functionally, the disordered proteins localized in the most disorder-enriched subcellular compartments are primarily responsible for interactions with nucleic acids and protein partners. This is the first-time disorder is comprehensively mapped into the human cell. Our observations add a missing piece to the puzzle of functional disorder and its organization inside the cell.

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Funding

This research was supported in part by the National Science Foundation (Grant 1617369) and the Robert J. Mattauch Endowment funds.

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Authors and Affiliations

  1. Department of Computer Science, Virginia Commonwealth University, 401 West Main Street, Room E4225, Richmond, VA, 23284, USA

    Bi Zhao, Akila Katuwawala & Lukasz Kurgan

  2. Department of Molecular Medicine, USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd. MDC07, Tampa, FL, 33612, USA

    Vladimir N. Uversky

  3. Laboratory of New Methods in Biology, Institute for Biological Instrumentation of the Russian Academy of Sciences, Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, Pushchino, Russia

    Vladimir N. Uversky

Authors
  1. Bi Zhao
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  2. Akila Katuwawala
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  3. Vladimir N. Uversky
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  4. Lukasz Kurgan
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Correspondence to Vladimir N. Uversky or Lukasz Kurgan.

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Zhao, B., Katuwawala, A., Uversky, V.N. et al. IDPology of the living cell: intrinsic disorder in the subcellular compartments of the human cell. Cell. Mol. Life Sci. 78, 2371–2385 (2021). https://doi.org/10.1007/s00018-020-03654-0

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  • DOI: https://doi.org/10.1007/s00018-020-03654-0

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