IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v11y2020i1d10.1038_s41467-020-18708-x.html
   My bibliography  Save this article

Structural basis for substrate recognition and chemical inhibition of oncogenic MAGE ubiquitin ligases

Author

Listed:
  • Seung Wook Yang

    (St. Jude Children’s Research Hospital)

  • Xin Huang

    (St. Jude Children’s Research Hospital)

  • Wenwei Lin

    (St. Jude Children’s Research Hospital)

  • Jaeki Min

    (St. Jude Children’s Research Hospital)

  • Darcie J. Miller

    (St. Jude Children’s Research Hospital)

  • Anand Mayasundari

    (St. Jude Children’s Research Hospital)

  • Patrick Rodrigues

    (St. Jude Children’s Research Hospital)

  • Elizabeth C. Griffith

    (St. Jude Children’s Research Hospital)

  • Clifford T. Gee

    (St. Jude Children’s Research Hospital)

  • Lei Li

    (University of California Irvine)

  • Wei Li

    (University of California Irvine)

  • Richard E. Lee

    (St. Jude Children’s Research Hospital)

  • Zoran Rankovic

    (St. Jude Children’s Research Hospital)

  • Taosheng Chen

    (St. Jude Children’s Research Hospital)

  • Patrick Ryan Potts

    (St. Jude Children’s Research Hospital)

Abstract

Testis-restricted melanoma antigen (MAGE) proteins are frequently hijacked in cancer and play a critical role in tumorigenesis. MAGEs assemble with E3 ubiquitin ligases and function as substrate adaptors that direct the ubiquitination of novel targets, including key tumor suppressors. However, how MAGEs recognize their targets is unknown and has impeded the development of MAGE-directed therapeutics. Here, we report the structural basis for substrate recognition by MAGE ubiquitin ligases. Biochemical analysis of the degron motif recognized by MAGE-A11 and the crystal structure of MAGE-A11 bound to the PCF11 substrate uncovered a conserved substrate binding cleft (SBC) in MAGEs. Mutation of the SBC disrupted substrate recognition by MAGEs and blocked MAGE-A11 oncogenic activity. A chemical screen for inhibitors of MAGE-A11:substrate interaction identified 4-Aminoquinolines as potent inhibitors of MAGE-A11 that show selective cytotoxicity. These findings provide important insights into the large family of MAGE ubiquitin ligases and identify approaches for developing cancer-specific therapeutics.

Suggested Citation

  • Seung Wook Yang & Xin Huang & Wenwei Lin & Jaeki Min & Darcie J. Miller & Anand Mayasundari & Patrick Rodrigues & Elizabeth C. Griffith & Clifford T. Gee & Lei Li & Wei Li & Richard E. Lee & Zoran Ran, 2020. "Structural basis for substrate recognition and chemical inhibition of oncogenic MAGE ubiquitin ligases," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18708-x
    DOI: 10.1038/s41467-020-18708-x
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-020-18708-x
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-020-18708-x?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
    ---><---

    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:11:y:2020:i:1:d:10.1038_s41467-020-18708-x. 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.

    We have no bibliographic references for this item. You can help adding them by using 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.