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Structure of E3 ligase E6AP with a proteasome-binding site provided by substrate receptor hRpn10

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Listed:
  • Gwen R. Buel

    (National Cancer Institute)

  • Xiang Chen

    (National Cancer Institute)

  • Raj Chari

    (Frederick National Laboratory for Cancer Research)

  • Maura J. O’Neill

    (Frederick National Laboratory for Cancer Research)

  • Danielle L. Ebelle

    (National Cancer Institute)

  • Conor Jenkins

    (Frederick National Laboratory for Cancer Research)

  • Vinidhra Sridharan

    (National Cancer Institute)

  • Sergey G. Tarasov

    (National Cancer Institute)

  • Nadya I. Tarasova

    (National Cancer Institute)

  • Thorkell Andresson

    (Frederick National Laboratory for Cancer Research)

  • Kylie J. Walters

    (National Cancer Institute)

Abstract

Regulated proteolysis by proteasomes involves ~800 enzymes for substrate modification with ubiquitin, including ~600 E3 ligases. We report here that E6AP/UBE3A is distinguished from other E3 ligases by having a 12 nM binding site at the proteasome contributed by substrate receptor hRpn10/PSMD4/S5a. Intrinsically disordered by itself, and previously uncharacterized, the E6AP-binding domain in hRpn10 locks into a well-defined helical structure to form an intermolecular 4-helix bundle with the E6AP AZUL, which is unique to this E3. We thus name the hRpn10 AZUL-binding domain RAZUL. We further find in human cells that loss of RAZUL by CRISPR-based gene editing leads to loss of E6AP at proteasomes. Moreover, proteasome-associated ubiquitin is reduced following E6AP knockdown or displacement from proteasomes, suggesting that E6AP ubiquitinates substrates at or for the proteasome. Altogether, our findings indicate E6AP to be a privileged E3 for the proteasome, with a dedicated, high affinity binding site contributed by hRpn10.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15073-7
    DOI: 10.1038/s41467-020-15073-7
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