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An adaptive peptide-binding site in ubiquitin receptor hRpn13 revealed by structural studies

Author

Listed:
  • Bakar Hassan

    (National Institutes of Health)

  • Monika Chandravanshi

    (National Institutes of Health)

  • Martin Y. Ng

    (National Cancer Institute)

  • Hitendra Negi

    (National Institutes of Health)

  • Brice A. P. Wilson

    (National Cancer Institute)

  • Kylie J. Walters

    (National Institutes of Health)

Abstract

A pleckstrin-like receptor for ubiquitin (Pru) domain in hRpn13 binds ubiquitin and proteasome subunit hRpn2. Here, we report a crystal structure of Pru bound to amino acids at the extreme N-terminus (ENT) of recombinant hRpn13. ENT adopts a U shape with native sequence along one side where M1 is buried in a Pru W108-centered pocket, and non-native sequence along the other with main chain hydrogen bonding to a neighboring Pru of the crystal lattice. These ENT:Pru interactions are stable in molecular dynamics simulations even with inclusion of only one Pru. Our findings suggest that hRpn13 can form bidentate interactions with ubiquitinated substrates by binding to both ubiquitin chains and disordered sequences of substrates. Testing this model by solution nuclear magnetic resonance revealed Pru to bind weakly to various peptides, concurrent binding with ubiquitin, and ENT displacement by hRpn2, the latter required for substrate handoff to the proteasome ATPases.

Suggested Citation

  • Bakar Hassan & Monika Chandravanshi & Martin Y. Ng & Hitendra Negi & Brice A. P. Wilson & Kylie J. Walters, 2025. "An adaptive peptide-binding site in ubiquitin receptor hRpn13 revealed by structural studies," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60843-w
    DOI: 10.1038/s41467-025-60843-w
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    References listed on IDEAS

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    1. 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.
    2. Susan Fishbain & Sumit Prakash & Annie Herrig & Suzanne Elsasser & Andreas Matouschek, 2011. "Rad23 escapes degradation because it lacks a proteasome initiation region," Nature Communications, Nature, vol. 2(1), pages 1-9, September.
    3. 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.
    4. Gwen R. Buel & Xiang Chen & Raj Chari & Maura J. O’Neill & Danielle L. Ebelle & Conor Jenkins & Vinidhra Sridharan & Sergey G. Tarasov & Nadya I. Tarasova & Thorkell Andresson & Kylie J. Walters, 2020. "Structure of E3 ligase E6AP with a proteasome-binding site provided by substrate receptor hRpn10," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    5. 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.
    6. 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.
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