8jrp
Structure of E6AP-E6 complex in Att3 state
Structural highlights
FunctionVE6_HPV16 Plays a major role in the induction and maintenance of cellular transformation. Acts mainly as an oncoprotein by stimulating the destruction of many host cell key regulatory proteins. E6 associates with host E6-AP ubiquitin-protein ligase, and inactivates tumor suppressors TP53 and TP73 by targeting them to the 26S proteasome for degradation. In turn, DNA damage and chromosomal instabilities increase and lead to cell proliferation and cancer development. The complex E6/E6P targets several other substrates to degradation via the proteasome including host NFX1-91, a repressor of human telomerase reverse transcriptase (hTERT). The resulting increased expression of hTERT prevents the shortening of telomere length leading to cell immortalization. Other cellular targets including Bak, Fas-associated death domain-containing protein (FADD) and procaspase 8, are degraded by E6/E6AP causing inhibition of apoptosis. E6 also inhibits immune response by interacting with host IRF3 and TYK2. These interactions prevent IRF3 transcriptional activities and inhibit TYK2-mediated JAK-STAT activation by interferon alpha resulting in inhibition of the interferon signaling pathway.[1] [2] [3] 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[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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