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Recognition of high-risk HPV E6 oncoproteins by 14-3-3 proteins studied by interactomics and crystallography
Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2020.07.24.220376v1?rss=1
Authors: Gogl, G., Tugaeva, K. V., Eberling, P., Kostmann, C., Trave, G., Sluchanko, N. N.
Abstract:
In tumors induced by high-risk mucosal human papillomaviruses (hrm-HPVs), HPV E6 oncoproteins inhibit apoptotic processes and sustain cell proliferation. E6 from all hrm-HPVs harbor a C-terminal short PDZ domain-binding motif (PBM), whose phosphorylation down-regulates PDZ binding but triggers E6 binding to 14-3-3 proteins. Here we classify PBMs of E6 proteins depending on their principle ability to be phosphorylated and subsequently acquire a 14-3-3-binding motif III consensus, (pS/pT)XX-COOH. Systematic competitive fluorescence polarization measurements show that the PBMs from four selected E6 oncoproteins bind all seven human 14-3-3 isoforms with distinct, wide-ranging affinities, obeying remarkable trends assigned to 14-3-3 isoform specificity and small E6 sequence variations. We crystallized the hrm-HPV18 E6 PBM bound to 14-3-3{zeta}, revealing a 14-3-3-motif III complex at 1.9 [A] resolution. Using fluorescence polarization and crystallography, we also demonstrate that fusicoccin, a molecule that reinforces many known 14-3-3 complexes, destabilizes the 14-3-3-E6 interaction, indicating the druggability of that complex.
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By Multimodal LLCLink to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2020.07.24.220376v1?rss=1
Authors: Gogl, G., Tugaeva, K. V., Eberling, P., Kostmann, C., Trave, G., Sluchanko, N. N.
Abstract:
In tumors induced by high-risk mucosal human papillomaviruses (hrm-HPVs), HPV E6 oncoproteins inhibit apoptotic processes and sustain cell proliferation. E6 from all hrm-HPVs harbor a C-terminal short PDZ domain-binding motif (PBM), whose phosphorylation down-regulates PDZ binding but triggers E6 binding to 14-3-3 proteins. Here we classify PBMs of E6 proteins depending on their principle ability to be phosphorylated and subsequently acquire a 14-3-3-binding motif III consensus, (pS/pT)XX-COOH. Systematic competitive fluorescence polarization measurements show that the PBMs from four selected E6 oncoproteins bind all seven human 14-3-3 isoforms with distinct, wide-ranging affinities, obeying remarkable trends assigned to 14-3-3 isoform specificity and small E6 sequence variations. We crystallized the hrm-HPV18 E6 PBM bound to 14-3-3{zeta}, revealing a 14-3-3-motif III complex at 1.9 [A] resolution. Using fluorescence polarization and crystallography, we also demonstrate that fusicoccin, a molecule that reinforces many known 14-3-3 complexes, destabilizes the 14-3-3-E6 interaction, indicating the druggability of that complex.
Copy rights belong to original authors. Visit the link for more info