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

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 and Kylie J. Walters ()
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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

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15073-7

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