Journal Article

Structural insights into the functional mechanism of the ubiquitin ligase E6AP

Gao, Rongchao, Yu, Xuekui, Ye, Fei, Lin, Min, Wang, Zhen, Xu, Wenwen, Luo, Cheng, Wang, Qingxia, Fan, Fengying, Qiu, Jiaxuan, Li, Zhihai, Lv, Yixin

2024

Overview

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. The human papillomavirus (HPV) E6 oncoprotein hijacks the ligase activity of the host E6AP to ubiquitinate the tumor suppressor p53. Here, the authors show how the presence of the HPV E6 oncoprotein transforms the inactive E6AP monomer into an active dimer, providing a structural understanding of the physiological and pathophysiological mechanisms of E6AP function.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/28 / 631/45/474/2073 / 631/45/535/1258/1259 / 631/67/1858 / 82/80 / 82/83 / Angelman's syndrome / Autism / Cancer / Cervical cancer / Crystallography, X-Ray / Dimerization / Dimers / Helices / Human papillomavirus / Humanities and Social Sciences / Humans / Models, Molecular / Molecular structure / Monomers / multidisciplinary / Mutagenesis / Oncogene Proteins, Viral - chemistry / Oncogene Proteins, Viral - genetics / Oncogene Proteins, Viral - metabolism / Oncoproteins / Protein Binding / Protein Conformation, alpha-Helical / Protein Multimerization / Science / Science (multidisciplinary) / Substrates / Tumor suppressor genes / Tumor Suppressor Protein p53 - chemistry / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - metabolism / Tumors / Ubiquitin - chemistry / Ubiquitin - metabolism / Ubiquitin-protein ligase / Ubiquitin-Protein Ligases - chemistry / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - metabolism / Ubiquitination