IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-46644-7.html
   My bibliography  Save this article

A structure-based designed small molecule depletes hRpn13Pru and a select group of KEN box proteins

Author

Listed:
  • Xiuxiu Lu

    (National Cancer Institute, National Institutes of Health)

  • Monika Chandravanshi

    (National Cancer Institute, National Institutes of Health)

  • Venkata R. Sabbasani

    (National Institutes of Health)

  • Snehal Gaikwad

    (National Cancer Institute)

  • V. Keith Hughitt

    (National Cancer Institute)

  • Nana Gyabaah-Kessie

    (National Cancer Institute)

  • Bradley T. Scroggins

    (National Cancer Institute, National Institutes of Health)

  • Sudipto Das

    (Inc.)

  • Wazo Myint

    (Frederick National Laboratory for Cancer Research)

  • Michelle E. Clapp

    (Frederick National Laboratory for Cancer Research)

  • Charles D. Schwieters

    (National Institutes of Health)

  • Marzena A. Dyba

    (National Cancer Institute, National Institutes of Health)

  • Derek L. Bolhuis

    (The University of North Carolina at Chapel Hill)

  • Janusz W. Koscielniak

    (National Institutes of Health)

  • Thorkell Andresson

    (Inc.)

  • Michael J. Emanuele

    (The University of North Carolina at Chapel Hill)

  • Nicholas G. Brown

    (The University of North Carolina at Chapel Hill)

  • Hiroshi Matsuo

    (Frederick National Laboratory for Cancer Research)

  • Raj Chari

    (Frederick National Laboratory for Cancer Research)

  • Deborah E. Citrin

    (National Cancer Institute, National Institutes of Health)

  • Beverly A. Mock

    (National Cancer Institute)

  • Rolf E. Swenson

    (National Institutes of Health)

  • Kylie J. Walters

    (National Cancer Institute, National Institutes of Health)

Abstract

Proteasome subunit hRpn13 is partially proteolyzed in certain cancer cell types to generate hRpn13Pru by degradation of its UCHL5/Uch37-binding DEUBAD domain and retention of an intact proteasome- and ubiquitin-binding Pru domain. By using structure-guided virtual screening, we identify an hRpn13 binder (XL44) and solve its structure ligated to hRpn13 Pru by integrated X-ray crystallography and NMR to reveal its targeting mechanism. Surprisingly, hRpn13Pru is depleted in myeloma cells following treatment with XL44. TMT-MS experiments reveal a select group of off-targets, including PCNA clamp-associated factor PCLAF and ribonucleoside-diphosphate reductase subunit M2 (RRM2), that are similarly depleted by XL44 treatment. XL44 induces hRpn13-dependent apoptosis and also restricts cell viability by a PCLAF-dependent mechanism. A KEN box, but not ubiquitination, is required for XL44-induced depletion of PCLAF. Here, we show that XL44 induces ubiquitin-dependent loss of hRpn13Pru and ubiquitin-independent loss of select KEN box containing proteins.

Suggested Citation

  • Xiuxiu Lu & Monika Chandravanshi & Venkata R. Sabbasani & Snehal Gaikwad & V. Keith Hughitt & Nana Gyabaah-Kessie & Bradley T. Scroggins & Sudipto Das & Wazo Myint & Michelle E. Clapp & Charles D. Sch, 2024. "A structure-based designed small molecule depletes hRpn13Pru and a select group of KEN box proteins," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46644-7
    DOI: 10.1038/s41467-024-46644-7
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-46644-7
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-46644-7?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. Xin Wang & Youn-Sang Jung & Sohee Jun & Sunhye Lee & Wenqi Wang & Andrea Schneider & Young Sun Oh & Steven H. Lin & Bum-Joon Park & Junjie Chen & Khandan Keyomarsi & Jae-Il Park, 2016. "PAF-Wnt signaling-induced cell plasticity is required for maintenance of breast cancer cell stemness," Nature Communications, Nature, vol. 7(1), pages 1-13, April.
    2. Patrick Schreiner & Xiang Chen & Koraljka Husnjak & Leah Randles & Naixia Zhang & Suzanne Elsasser & Daniel Finley & Ivan Dikic & Kylie J. Walters & Michael Groll, 2008. "Ubiquitin docking at the proteasome through a novel pleckstrin-homology domain interaction," Nature, Nature, vol. 453(7194), pages 548-552, May.
    3. Xiuxiu Lu & Venkata R. Sabbasani & Vasty Osei-Amponsa & Christine N. Evans & Julianna C. King & Sergey G. Tarasov & Marzena Dyba & Sudipto Das & King C. Chan & Charles D. Schwieters & Sulbha Choudhari, 2021. "Structure-guided bifunctional molecules hit a DEUBAD-lacking hRpn13 species upregulated in multiple myeloma," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    4. Koraljka Husnjak & Suzanne Elsasser & Naixia Zhang & Xiang Chen & Leah Randles & Yuan Shi & Kay Hofmann & Kylie J. Walters & Daniel Finley & Ivan Dikic, 2008. "Proteasome subunit Rpn13 is a novel ubiquitin receptor," Nature, Nature, vol. 453(7194), pages 481-488, May.
    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. Xiuxiu Lu & Venkata R. Sabbasani & Vasty Osei-Amponsa & Christine N. Evans & Julianna C. King & Sergey G. Tarasov & Marzena Dyba & Sudipto Das & King C. Chan & Charles D. Schwieters & Sulbha Choudhari, 2021. "Structure-guided bifunctional molecules hit a DEUBAD-lacking hRpn13 species upregulated in multiple myeloma," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    2. Bongjun Kim & Yuanjian Huang & Kyung-Pil Ko & Shengzhe Zhang & Gengyi Zou & Jie Zhang & Moon Jong Kim & Danielle Little & Lisandra Vila Ellis & Margherita Paschini & Sohee Jun & Kwon-Sik Park & Jichao, 2024. "PCLAF-DREAM drives alveolar cell plasticity for lung regeneration," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Nathan Jespersen & Kai Ehrenbolger & Rahel R. Winiger & Dennis Svedberg & Charles R. Vossbrinck & Jonas Barandun, 2022. "Structure of the reduced microsporidian proteasome bound by PI31-like peptides in dormant spores," Nature Communications, Nature, vol. 13(1), pages 1-14, 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_s41467-024-46644-7. 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.