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Deep mutational scanning reveals a correlation between degradation and toxicity of thousands of aspartoacylase variants

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  • Martin Grønbæk-Thygesen

    (University of Copenhagen)

  • Vasileios Voutsinos

    (University of Copenhagen)

  • Kristoffer E. Johansson

    (University of Copenhagen)

  • Thea K. Schulze

    (University of Copenhagen)

  • Matteo Cagiada

    (University of Copenhagen)

  • Line Pedersen

    (University of Copenhagen)

  • Lene Clausen

    (University of Copenhagen)

  • Snehal Nariya

    (University of Washington)

  • Rachel L. Powell

    (University of Washington)

  • Amelie Stein

    (University of Copenhagen)

  • Douglas M. Fowler

    (University of Washington
    University of Washington)

  • Kresten Lindorff-Larsen

    (University of Copenhagen)

  • Rasmus Hartmann-Petersen

    (University of Copenhagen)

Abstract

Unstable proteins are prone to form non-native interactions with other proteins and thereby may become toxic. To mitigate this, destabilized proteins are targeted by the protein quality control network. Here we present systematic studies of the cytosolic aspartoacylase, ASPA, where variants are linked to Canavan disease, a lethal neurological disorder. We determine the abundance of 6152 of the 6260 ( ~ 98%) possible single amino acid substitutions and nonsense ASPA variants in human cells. Most low abundance variants are degraded through the ubiquitin-proteasome pathway and become toxic upon prolonged expression. The data correlates with predicted changes in thermodynamic stability, evolutionary conservation, and separate disease-linked variants from benign variants. Mapping of degradation signals (degrons) shows that these are often buried and the C-terminal region functions as a degron. The data can be used to interpret Canavan disease variants and provide insight into the relationship between protein stability, degradation and cell fitness.

Suggested Citation

  • Martin Grønbæk-Thygesen & Vasileios Voutsinos & Kristoffer E. Johansson & Thea K. Schulze & Matteo Cagiada & Line Pedersen & Lene Clausen & Snehal Nariya & Rachel L. Powell & Amelie Stein & Douglas M., 2024. "Deep mutational scanning reveals a correlation between degradation and toxicity of thousands of aspartoacylase variants," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48481-0
    DOI: 10.1038/s41467-024-48481-0
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    1. Lene Clausen & Vasileios Voutsinos & Matteo Cagiada & Kristoffer E. Johansson & Martin Grønbæk-Thygesen & Snehal Nariya & Rachel L. Powell & Magnus K. N. Have & Vibe H. Oestergaard & Amelie Stein & Do, 2024. "A mutational atlas for Parkin proteostasis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Rahul S. Samant & Christine M. Livingston & Emily M. Sontag & Judith Frydman, 2018. "Distinct proteostasis circuits cooperate in nuclear and cytoplasmic protein quality control," Nature, Nature, vol. 563(7731), pages 407-411, November.
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    5. Matteo Cagiada & Sandro Bottaro & Søren Lindemose & Signe M. Schenstrøm & Amelie Stein & Rasmus Hartmann-Petersen & Kresten Lindorff-Larsen, 2023. "Discovering functionally important sites in proteins," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
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