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A mutational atlas for Parkin proteostasis

Author

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  • Lene Clausen

    (Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen)

  • Vasileios Voutsinos

    (Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen)

  • Matteo Cagiada

    (Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen)

  • Kristoffer E. Johansson

    (Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen)

  • Martin Grønbæk-Thygesen

    (Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen)

  • Snehal Nariya

    (University of Washington)

  • Rachel L. Powell

    (University of Washington)

  • Magnus K. N. Have

    (Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen)

  • Vibe H. Oestergaard

    (University of Copenhagen)

  • Amelie Stein

    (University of Copenhagen)

  • Douglas M. Fowler

    (University of Washington
    University of Washington)

  • Kresten Lindorff-Larsen

    (Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen)

  • Rasmus Hartmann-Petersen

    (Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen)

Abstract

Proteostasis can be disturbed by mutations affecting folding and stability of the encoded protein. An example is the ubiquitin ligase Parkin, where gene variants result in autosomal recessive Parkinsonism. To uncover the pathological mechanism and provide comprehensive genotype-phenotype information, variant abundance by massively parallel sequencing (VAMP-seq) is leveraged to quantify the abundance of Parkin variants in cultured human cells. The resulting mutational map, covering 9219 out of the 9300 possible single-site amino acid substitutions and nonsense Parkin variants, shows that most low abundance variants are proteasome targets and are located within the structured domains of the protein. Half of the known disease-linked variants are found at low abundance. Systematic mapping of degradation signals (degrons) reveals an exposed degron region proximal to the so-called “activation element”. This work provides examples of how missense variants may cause degradation either via destabilization of the native protein, or by introducing local signals for degradation.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45829-4
    DOI: 10.1038/s41467-024-45829-4
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    1. Tohru Kitada & Shuichi Asakawa & Nobutaka Hattori & Hiroto Matsumine & Yasuhiro Yamamura & Shinsei Minoshima & Masayuki Yokochi & Yoshikuni Mizuno & Nobuyoshi Shimizu, 1998. "Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism," Nature, Nature, vol. 392(6676), pages 605-608, April.
    2. Kotaro Tsuboyama & Justas Dauparas & Jonathan Chen & Elodie Laine & Yasser Mohseni Behbahani & Jonathan J. Weinstein & Niall M. Mangan & Sergey Ovchinnikov & Gabriel J. Rocklin, 2023. "Mega-scale experimental analysis of protein folding stability in biology and design," Nature, Nature, vol. 620(7973), pages 434-444, August.
    3. Tobias Wauer & Michal Simicek & Alexander Schubert & David Komander, 2015. "Mechanism of phospho-ubiquitin-induced PARKIN activation," Nature, Nature, vol. 524(7565), pages 370-374, August.
    4. Christina Gladkova & Sarah L. Maslen & J. Mark Skehel & David Komander, 2018. "Mechanism of parkin activation by PINK1," Nature, Nature, vol. 559(7714), pages 410-414, July.
    5. Jonathan Frazer & Pascal Notin & Mafalda Dias & Aidan Gomez & Joseph K. Min & Kelly Brock & Yarin Gal & Debora S. Marks, 2021. "Disease variant prediction with deep generative models of evolutionary data," Nature, Nature, vol. 599(7883), pages 91-95, November.
    6. Tobias Wauer & Michal Simicek & Alexander Schubert & David Komander, 2015. "Erratum: Mechanism of phospho-ubiquitin-induced PARKIN activation," Nature, Nature, vol. 526(7575), pages 728-728, October.
    7. Fumika Koyano & Kei Okatsu & Hidetaka Kosako & Yasushi Tamura & Etsu Go & Mayumi Kimura & Yoko Kimura & Hikaru Tsuchiya & Hidehito Yoshihara & Takatsugu Hirokawa & Toshiya Endo & Edward A. Fon & Jean-, 2014. "Ubiquitin is phosphorylated by PINK1 to activate parkin," Nature, Nature, vol. 510(7503), pages 162-166, June.
    8. Konrad J. Karczewski & Laurent C. Francioli & Grace Tiao & Beryl B. Cummings & Jessica Alföldi & Qingbo Wang & Ryan L. Collins & Kristen M. Laricchia & Andrea Ganna & Daniel P. Birnbaum & Laura D. Gau, 2020. "The mutational constraint spectrum quantified from variation in 141,456 humans," Nature, Nature, vol. 581(7809), pages 434-443, May.
    9. Shireen A. Sarraf & Malavika Raman & Virginia Guarani-Pereira & Mathew E. Sowa & Edward L. Huttlin & Steven P. Gygi & J. Wade Harper, 2013. "Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization," Nature, Nature, vol. 496(7445), pages 372-376, April.
    10. 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.
    11. Bayan Mashahreh & Shir Armony & Kristoffer Enøe Johansson & Alon Chappleboim & Nir Friedman & Richard G. Gardner & Rasmus Hartmann-Petersen & Kresten Lindorff-Larsen & Tommer Ravid, 2022. "Conserved degronome features governing quality control associated proteolysis," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
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    1. 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.

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