On April 26, Researcher Yu Xuekui and his team from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, in collaboration with researcher Luo Cheng, utilized cryo-electron microscopy to elucidate the structures of the HECT-type ubiquitin ligase family E6AP protein and the complex of human papillomavirus (HPV) oncoprotein E6 binding to E6AP in different conformations. Through molecular dynamics simulation analysis and biochemical experiments, they systematically revealed the molecular mechanism of dynamic regulation of E6AP activity. The related research was published in "Nature Communications."
E6 hijacks the ubiquitin ligase activity of E6AP, leading to abnormal ubiquitination and degradation of the tumor suppressor p53, which is associated with the occurrence and development of various HPV-positive cancers. Additionally, the loss/weakening and enhancement of E6AP activity are respectively related to Angelman syndrome and autism spectrum disorders.
By using cryo-electron microscopy, the research team resolved the high-resolution structure of the E6AP/E6 binary complex, discovering a novel assembly mode of the complex. They successfully captured five different spatial conformations, suggesting that the complex structure represents a continuum of conformations for ubiquitin transfer. Functional experiments further revealed the structural basis for E6AP-mediated substrate ubiquitination, leading to the elucidation of the cryo-electron microscopy structure of the full-length monomer of E6AP.
Based on this, the research team proposed for the first time a dynamic regulation mechanism of E6 on E6AP enzyme activity. They found that some E6AP mutations associated with Angelman syndrome and autism spectrum disorders are located in the extended α1-helix region, suggesting that these mutations may affect the stability of α1-helix, thereby leading to functional impairment of E6AP.
The image is from "Nature Communications."
Related paper information: https://doi.org/10.1038/s41467-024-47586-w
