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.

E6AP 功能障碍与天使综合征和自闭症谱系障碍有关。此外，宿主 E6AP 被高危 HPV E6 劫持，使肿瘤抑制因子 p53 异常泛素化，这与多种癌症（包括大多数宫颈癌）的发生有关。在这里，我们表明E6AP和E6AP/E6复合物分别作为E6AP/E6原聚体的单体和二聚体存在。当与 E6 复合时，E6AP 的短 α1 螺旋转变为较长的螺旋结构。二聚体的延伸 α1-螺旋对称交叉并有助于二聚化。两个原体围绕两个 α1 螺旋的交叉区域摆动，促进底物与 E6AP 催化 C 叶的附着和分离，从而促进泛素转移。这些发现加上诱变分析表明，α1 螺旋通过构象转变控制 E6AP 的非活性单体和活性二聚体之间的转变。