Lysine deserts prevent adventitious ubiquitylation of ubiquitin-proteasome components

Caroline Kampmeyer, Martin Grønbæk-Thygesen, Nicole Oelerich, Michael H. Tatham, Matteo Cagiada, Kresten Lindorff-Larsen, Wouter Boomsma (Lead / Corresponding author), Kay Hofmann (Lead / Corresponding author), Rasmus Hartmann-Petersen (Lead / Corresponding author)

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    2 Citations (Scopus)
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    In terms of its relative frequency, lysine is a common amino acid in the human proteome. However, by bioinformatics we find hundreds of proteins that contain long and evolutionarily conserved stretches completely devoid of lysine residues. These so-called lysine deserts show a high prevalence in intrinsically disordered proteins with known or predicted functions within the ubiquitin-proteasome system (UPS), including many E3 ubiquitin-protein ligases and UBL domain proteasome substrate shuttles, such as BAG6, RAD23A, UBQLN1 and UBQLN2. We show that introduction of lysine residues into the deserts leads to a striking increase in ubiquitylation of some of these proteins. In case of BAG6, we show that ubiquitylation is catalyzed by the E3 RNF126, while RAD23A is ubiquitylated by E6AP. Despite the elevated ubiquitylation, mutant RAD23A appears stable, but displays a partial loss of function phenotype in fission yeast. In case of UBQLN1 and BAG6, introducing lysine leads to a reduced abundance due to proteasomal degradation of the proteins. For UBQLN1 we show that arginine residues within the lysine depleted region are critical for its ability to form cytosolic speckles/inclusions. We propose that selective pressure to avoid lysine residues may be a common evolutionary mechanism to prevent unwarranted ubiquitylation and/or perhaps other lysine post-translational modifications. This may be particularly relevant for UPS components as they closely and frequently encounter the ubiquitylation machinery and are thus more susceptible to nonspecific ubiquitylation.

    Original languageEnglish
    Article number143
    Number of pages18
    JournalCellular and molecular life sciences : CMLS
    Issue number6
    Publication statusPublished - 9 May 2023


    • Humans
    • Proteasome Endopeptidase Complex
    • Ubiquitin
    • Lysine
    • Cytoplasm
    • Ubiquitination
    • Schizosaccharomyces/genetics
    • Molecular Chaperones
    • Autophagy-Related Proteins
    • Adaptor Proteins, Signal Transducing
    • Ubiquitin-Protein Ligases
    • PTM
    • Degradation
    • Intrinsically disordered protein
    • Proteasome

    ASJC Scopus subject areas

    • Cellular and Molecular Neuroscience
    • Molecular Medicine
    • Molecular Biology
    • Cell Biology
    • Pharmacology


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