IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-49489-2.html
   My bibliography  Save this article

N-terminal cysteine acetylation and oxidation patterns may define protein stability

Author

Listed:
  • Karen C. Heathcote

    (University of Oxford
    University of Oxford
    The Francis Crick Institute)

  • Thomas P. Keeley

    (University of Oxford)

  • Matti Myllykoski

    (University of Bergen)

  • Malin Lundekvam

    (University of Bergen)

  • Nina McTiernan

    (University of Bergen)

  • Salma Akter

    (University of Oxford)

  • Norma Masson

    (University of Oxford)

  • Peter J. Ratcliffe

    (University of Oxford
    The Francis Crick Institute)

  • Thomas Arnesen

    (University of Bergen
    Haukeland University Hospital)

  • Emily Flashman

    (University of Oxford)

Abstract

Oxygen homeostasis is maintained in plants and animals by O2-sensing enzymes initiating adaptive responses to low O2 (hypoxia). Recently, the O2-sensitive enzyme ADO was shown to initiate degradation of target proteins RGS4/5 and IL32 via the Cysteine/Arginine N-degron pathway. ADO functions by catalysing oxidation of N-terminal cysteine residues, but despite multiple proteins in the human proteome having an N-terminal cysteine, other endogenous ADO substrates have not yet been identified. This could be because alternative modifications of N-terminal cysteine residues, including acetylation, prevent ADO-catalysed oxidation. Here we investigate the relationship between ADO-catalysed oxidation and NatA-catalysed acetylation of a broad range of protein sequences with N-terminal cysteines. We present evidence that human NatA catalyses N-terminal cysteine acetylation in vitro and in vivo. We then show that sequences downstream of the N-terminal cysteine dictate whether this residue is oxidised or acetylated, with ADO preferring basic and aromatic amino acids and NatA preferring acidic or polar residues. In vitro, the two modifications appear to be mutually exclusive, suggesting that distinct pools of N-terminal cysteine proteins may be acetylated or oxidised. These results reveal the sequence determinants that contribute to N-terminal cysteine protein modifications, with implications for O2-dependent protein stability and the hypoxic response.

Suggested Citation

  • Karen C. Heathcote & Thomas P. Keeley & Matti Myllykoski & Malin Lundekvam & Nina McTiernan & Salma Akter & Norma Masson & Peter J. Ratcliffe & Thomas Arnesen & Emily Flashman, 2024. "N-terminal cysteine acetylation and oxidation patterns may define protein stability," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49489-2
    DOI: 10.1038/s41467-024-49489-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-49489-2
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-49489-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Daan A. Weits & Beatrice Giuntoli & Monika Kosmacz & Sandro Parlanti & Hans-Michael Hubberten & Heike Riegler & Rainer Hoefgen & Pierdomenico Perata & Joost T. van Dongen & Francesco Licausi, 2014. "Plant cysteine oxidases control the oxygen-dependent branch of the N-end-rule pathway," Nature Communications, Nature, vol. 5(1), pages 1-10, May.
    2. Francesco Licausi & Monika Kosmacz & Daan A. Weits & Beatrice Giuntoli & Federico M. Giorgi & Laurentius A. C. J. Voesenek & Pierdomenico Perata & Joost T. van Dongen, 2011. "Oxygen sensing in plants is mediated by an N-end rule pathway for protein destabilization," Nature, Nature, vol. 479(7373), pages 419-422, November.
    3. Sylvia Varland & Rui Duarte Silva & Ine Kjosås & Alexandra Faustino & Annelies Bogaert & Maximilian Billmann & Hadi Boukhatmi & Barbara Kellen & Michael Costanzo & Adrian Drazic & Camilla Osberg & Kat, 2023. "N-terminal acetylation shields proteins from degradation and promotes age-dependent motility and longevity," Nature Communications, Nature, vol. 14(1), pages 1-27, December.
    4. Eric Linster & Francy L. Forero Ruiz & Pavlina Miklankova & Thomas Ruppert & Johannes Mueller & Laura Armbruster & Xiaodi Gong & Giovanna Serino & Matthias Mann & Rüdiger Hell & Markus Wirtz, 2022. "Cotranslational N-degron masking by acetylation promotes proteome stability in plants," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    5. Mark D. White & Maria Klecker & Richard J. Hopkinson & Daan A. Weits & Carolin Mueller & Christin Naumann & Rebecca O’Neill & James Wickens & Jiayu Yang & Jonathan C. Brooks-Bartlett & Elspeth F. Garm, 2017. "Plant cysteine oxidases are dioxygenases that directly enable arginyl transferase-catalysed arginylation of N-end rule targets," Nature Communications, Nature, vol. 8(1), pages 1-9, April.
    6. Daniel J. Gibbs & Seung Cho Lee & Nurulhikma Md Isa & Silvia Gramuglia & Takeshi Fukao & George W. Bassel & Cristina Sousa Correia & Françoise Corbineau & Frederica L. Theodoulou & Julia Bailey-Serres, 2011. "Homeostatic response to hypoxia is regulated by the N-end rule pathway in plants," Nature, Nature, vol. 479(7373), pages 415-418, November.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Agata Zubrycka & Charlene Dambire & Laura Dalle Carbonare & Gunjan Sharma & Tinne Boeckx & Kamal Swarup & Craig J. Sturrock & Brian S. Atkinson & Ranjan Swarup & Françoise Corbineau & Neil J. Oldham &, 2023. "ERFVII action and modulation through oxygen-sensing in Arabidopsis thaliana," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Verna Van & Janae B. Brown & Corin R. O’Shea & Hannah Rosenbach & Ijaz Mohamed & Nna-Emeka Ejimogu & Toan S. Bui & Veronika A. Szalai & Kelly N. Chacón & Ingrid Span & Fangliang Zhang & Aaron T. Smith, 2023. "Iron-sulfur clusters are involved in post-translational arginylation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Charlotte M. François & Thomas Pihl & Marion Dunoyer de Segonzac & Chloé Hérault & Bruno Hudry, 2023. "Metabolic regulation of proteome stability via N-terminal acetylation controls male germline stem cell differentiation and reproduction," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. Sylvia Varland & Rui Duarte Silva & Ine Kjosås & Alexandra Faustino & Annelies Bogaert & Maximilian Billmann & Hadi Boukhatmi & Barbara Kellen & Michael Costanzo & Adrian Drazic & Camilla Osberg & Kat, 2023. "N-terminal acetylation shields proteins from degradation and promotes age-dependent motility and longevity," Nature Communications, Nature, vol. 14(1), pages 1-27, December.
    5. Eric Linster & Francy L. Forero Ruiz & Pavlina Miklankova & Thomas Ruppert & Johannes Mueller & Laura Armbruster & Xiaodi Gong & Giovanna Serino & Matthias Mann & Rüdiger Hell & Markus Wirtz, 2022. "Cotranslational N-degron masking by acetylation promotes proteome stability in plants," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    6. Yao Li & Yueling Zhao & Xiaojie Yan & Chen Ye & Sara Weirich & Bing Zhang & Xiaolu Wang & Lili Song & Chenhao Jiang & Albert Jeltsch & Cheng Dong & Wenyi Mi, 2022. "CRL2ZER1/ZYG11B recognizes small N-terminal residues for degradation," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    7. Hongliang Zhang & Julia Quintana & Koray Ütkür & Lorenz Adrian & Harmen Hawer & Klaus Mayer & Xiaodi Gong & Leonardo Castanedo & Anna Schulten & Nadežda Janina & Marcus Peters & Markus Wirtz & Ulrich , 2022. "Translational fidelity and growth of Arabidopsis require stress-sensitive diphthamide biosynthesis," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    8. Ulises H. Guzman & Henriette Aksnes & Rasmus Ree & Nicolai Krogh & Magnus E. Jakobsson & Lars J. Jensen & Thomas Arnesen & Jesper V. Olsen, 2023. "Loss of N-terminal acetyltransferase A activity induces thermally unstable ribosomal proteins and increases their turnover in Saccharomyces cerevisiae," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    9. Viorica Chelban & Henriette Aksnes & Reza Maroofian & Lauren C. LaMonica & Luis Seabra & Anette Siggervåg & Perrine Devic & Hanan E. Shamseldin & Jana Vandrovcova & David Murphy & Anne-Claire Richard , 2024. "Biallelic NAA60 variants with impaired N-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49489-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.