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• W3104398410 abstract "The high-risk human alpha papillomaviruses, associated with the development of cervical cancer differ in the carboxyl-terminal sequence of the E6 oncogenic protein, where a PDZ-binding motif (PBM) is located. The PBM binds to PDZ-containing proteins of the cell, and variation in the PBM sequence is likely to affect the PDZ protein selectivity of E6, and the phospho-acceptor site embedded within the PBM. Using the E6 proteins from HPV types with diverse phylogenetic and risk classifications, we found that differences in their PBMs are reflected in their substrate selection. Moreover, we show that the ability of E6 proteins to target PDZ proteins has co-evolved with the phospho-regulation of the PBMs.Previously identified residues known to reduce both HPV-18 phosphorylation and its functional flexibility in substrate selection, were mutated in the core and upstream regions of HPV-66 and HPV-40 E6 PBMs to generate phospho-acceptor sites for CHK1, PKA and AKT kinases. The patterns of binding to PDZ proteins by these mutants were then evaluated. I found that the last residue of HPV-18 E6 (Valine) is critical for its recognition of MAGI-1 and when the last residue of HPV-40 E6 (Cysteine) is mutated to Valine, it increases HPV-40 E6's PBM-dependent binding to MAGI-1 in pull-down assays. This was also confirmed with Dlg1. As expected, the reverse (Valine to Cysteine) substitution in the HPV-18 E6 PBM also destroys its binding to Scribble, but the Cysteine to Valine substitution failed to confer Scribble binding on HPV-40, suggesting that additional critical residues are required for Scribble recognition. Additionally, we evaluated the phosphorylation of the HPV-66 E6 protein by the three kinases, introducing arginine residues on the p-4 and p-5 positions of the PBM. The wild-type HPV-66 E6 protein is not phosphorylated, as well as the p-5 mutant. On the contrary, mutations on p-4 and p-4/p-5 positions have increased phosphorylation by PKA, slightly by CHK1 but not by AKT. Mutations on p-5 position resulted in a mild increase in recognition of MAGI-1 whilst surprisingly mutations on p-4 which confers phosphorylation, does not. The arginine residue substitutions resulted in a mild increase of the ability of the HPV-66 E6 PBM to bind Dlg1, and failed to confer interaction with Scribble; again, suggesting the involvement of additional residues.Moreover, we used HPV-16 E6 protein to further evaluate if residues upstream of the PBM are important for binding PDZ proteins and whether upstream phosphor acceptor sites might regulate PDZ recognition. We evaluated a threonine residue on p-6 position and found that this position is phosphorylated by CK1 kinase with lowerefficiency. Furthermore, the Aspartate substitution mildly increased binding to TIP-1 and SNTB2 PDZ proteins, and conversely, the Alanine substitution significantly decreased binding. Furthermore, we observed that a triplet of serine residues on positions p-8, p-9 and p-13 upstream of the PBM can be multiply phosphorylated by PKC and CK1 kinases. The multiple Aspartate substitution mutant showed higher retention of E6 in the cytoplasm, and the Alanine substitution mutant higher retention in the nucleus, indicating that phosphorylation of these residues might modulate E6 localisation. Taken together these studies demonstrate a unique linkage between evolution of the phospho-acceptor site embedded in the PBM and functional flexibility, together with further regulation provided by potentially unique phospho-acceptor sites only found in HPV-16 E6.Finally, we evaluated the capacity of the low-risk HPV-11, a less potent version of the HR types, but a common cause of benign tumours in the anogenital region and the upper respiratory tract, rarely associated with cancer, to degrade p53. Although, 11E6 can bind E6AP and p53, it binds the carboxy-terminal site of p53, and not the core domain that is necessary for degradation induced by the E6 of high-risk types. Regardless, a recent report has shown that HPV-11 E6 degrades p53 under high-confluency conditions, suggesting a conserved and common mechanism between high- and low-risk types. We showed in Part 3, that HPV-11 E6 degrades p53 after treatment with etoposide, a DNA damaging agent. It has been shown that Etoposide induces the phosphorylation of p53 on serine 15, an important and nucleating event in p53 activation through post-translational modifications. Furthermore, 11E6 induces the degradation of the p53 phospho-mimic mutant S15D, which mimics the activated form of p53 and which is not susceptible to Mdm2-induced degradation. Moreover, we confirmed that 11E6 co-localizes with p53 after the treatment with Etoposide, and with the p53 S15D phospho-mimic mutant. Interestingly, we observed that 11E6 influences the cellular distribution of wild type p53 to the cytoplasm, when transiently co-transfected together, as with the phospho-mimic mutant. We hypothesized that the common ancestor of high- and low-risk types might have been able to degrade specific forms of p53, and that eventually, the high-risk types developed the ability to degrade all forms of p53, contributing to their oncogenic potential. Whether 11E6’s specific ability to induce degradation of Ser15 phospho-p53 is related to HPV-11’s successful replication and maintenance within the cell needs investigating." @default.
• W3104398410 created "2020-11-23" @default.
• W3104398410 creator A5013466688 @default.
• W3104398410 date "2020-09-14" @default.
• W3104398410 modified "2023-09-23" @default.
• W3104398410 title "Towards an understanding of the evolution of the HPV E6 PDZ binding motif" @default.
• W3104398410 hasPublicationYear "2020" @default.
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