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Structure of E6AP-E6 complex in Att2 stateStructure of E6AP-E6 complex in Att2 state
Structural highlights
DiseaseUBE3A_HUMAN Defects in UBE3A are a cause of Angelman syndrome (AS) [MIM:105830; also known as 'happy puppet syndrome'. AS is characterized by features of severe motor and intellectual retardation, microcephaly, ataxia, frequent jerky limb movements and flapping of the arms and hands, hypotonia, hyperactivity, hypopigmentation, seizures, absence of speech, frequent smiling and episodes of paroxysmal laughter, and an unusual facies characterized by macrostomia, a large mandible and open-mouthed expression, a great propensity for protruding the tongue ('tongue thrusting'), and an occipital groove.[1] [2] FunctionUBE3A_HUMAN E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and transfers it to its substrates. Several substrates have been identified including the RAD23A and RAD23B, MCM7 (which is involved in DNA replication), annexin A1, the PML tumor suppressor, and the cell cycle regulator CDKN1B. Catalyzes the high-risk human papilloma virus E6-mediated ubiquitination of p53/TP53, contributing to the neoplastic progression of cells infected by these viruses. Additionally, may function as a cellular quality control ubiquitin ligase by helping the degradation of the cytoplasmic misfolded proteins. Finally, UBE3A also promotes its own degradation in vivo.[3] [4] [5] [6] [7] [8] Publication Abstract from PubMedE6AP 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 alpha1-helix of E6AP transforms into a longer helical structure when in complex with E6. The extended alpha1-helices of the dimer intersect symmetrically and contribute to the dimerization. The two protomers sway around the crossed region of the two alpha1-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 alpha1-helix, through conformational transformations, controls the transition between the inactive monomer and the active dimer of E6AP. Structural insights into the functional mechanism of the ubiquitin ligase E6AP.,Wang Z, Fan F, Li Z, Ye F, Wang Q, Gao R, Qiu J, Lv Y, Lin M, Xu W, Luo C, Yu X Nat Commun. 2024 Apr 26;15(1):3531. doi: 10.1038/s41467-024-47586-w. PMID:38670961[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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