Structural insights into the functional mechanism of the ubiquitin ligase E6AP

Zhen Wang, Fengying Fan, Zhihai Li, Fei Ye, Qingxia Wang, Rongchao Gao, Jiaxuan Qiu, Yixin Lv, Min Lin, Wenwen Xu, Cheng Luo () and Xuekui Yu ()
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Zhen Wang: Chinese Academy of Sciences
Fengying Fan: Chinese Academy of Sciences
Zhihai Li: University of Chinese Academy of Sciences
Fei Ye: Zhejiang Sci-Tech University
Qingxia Wang: Chinese Academy of Sciences
Rongchao Gao: Chinese Academy of Sciences
Jiaxuan Qiu: Chinese Academy of Sciences
Yixin Lv: University of Chinese Academy of Sciences
Min Lin: Zhejiang Sci-Tech University
Wenwen Xu: Chinese Academy of Sciences
Cheng Luo: Chinese Academy of Sciences
Xuekui Yu: Chinese Academy of Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract E6AP dysfunction is associated with Angelman syndrome and Autism spectrum disorder. Additionally, the host E6AP is hijacked by the high-risk HPV E6 to aberrantly ubiquitinate the tumor suppressor p53, which is linked with development of multiple types of cancer, including most cervical cancers. Here we show that E6AP and the E6AP/E6 complex exist, respectively, as a monomer and a dimer of the E6AP/E6 protomer. The short α1-helix of E6AP transforms into a longer helical structure when in complex with E6. The extended α1-helices of the dimer intersect symmetrically and contribute to the dimerization. The two protomers sway around the crossed region of the two α1-helices to promote the attachment and detachment of substrates to the catalytic C-lobe of E6AP, thus facilitating ubiquitin transfer. These findings, complemented by mutagenesis analysis, suggest that the α1-helix, through conformational transformations, controls the transition between the inactive monomer and the active dimer of E6AP.

Date: 2024
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DOI: 10.1038/s41467-024-47586-w

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