Molecular dissection of the E6 PBM identifies essential residues regulating Chk1 phosphorylation and subsequent 14-3-3 recognition

IF 4.7 Q1 VIROLOGY Tumour Virus Research Pub Date : 2023-06-01 DOI:10.1016/j.tvr.2023.200257
Arushi Vats , Jayashree V. Thatte , Lawrence Banks
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Abstract

Previous studies have shown that the high-risk HPV E6 oncoprotein PDZ binding motifs (PBMs) can interact with PDZ proteins or members of the 14-3-3 family, depending upon the E6 phosphorylation status. However, different HPV E6 oncoproteins are subjected to phosphorylation by different cellular kinases. We have therefore been interested in determining whether we can dissect E6's PDZ and 14-3-3 interactions at the molecular level. Using HPV-18 E6, we have found that its Chk1 phosphorylation requires residues both upstream and downstream of the phospho-acceptor site, in addition to the Chk1 consensus recognition motif. Furthermore, we demonstrate that different high-risk HPV E6 types are differentially phosphorylated by Chk1 kinases, potentially due to the differences in their carboxy-terminal residues, as they are critical for kinase recognition. Moreover, differences in the E6 phosphorylation levels of different HR HPV types directly link to their ability to interact with different 14-3-3 isoforms, based on their phospho-status. Interestingly, 14-3-3 recognition appears to be less dependent upon the precise sequence constraints of the E6 carboxy terminal region, whilst minor amino acid variations have a major impact upon PDZ recognition. These results demonstrate that changes in E6 phospho-status during the life cycle or during malignant progression will modulate E6 interactions and, potentially, inversely regulate the levels of PDZ and 14-3-3 proteins.

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E6 PBM的分子解剖鉴定了调节Chk1磷酸化和随后的14-3-3识别的必要残基
先前的研究表明,高危HPV E6癌蛋白PDZ结合基序(PBMs)可以与PDZ蛋白或14-3-3家族成员相互作用,这取决于E6磷酸化状态。然而,不同的HPV E6癌蛋白被不同的细胞激酶磷酸化。因此,我们一直有兴趣确定我们是否可以在分子水平上剖析E6的PDZ和14-3-3相互作用。使用HPV-18 E6,我们发现其Chk1磷酸化除了Chk1共有识别基序外,还需要磷酸化受体位点上游和下游的残基。此外,我们证明了不同的高危HPV E6类型被Chk1激酶不同地磷酸化,这可能是由于其羧基末端残基的差异,因为它们对激酶识别至关重要。此外,不同HR HPV类型E6磷酸化水平的差异直接与它们基于磷酸化状态与不同14-3-3亚型相互作用的能力有关。有趣的是,14-3-3的识别似乎较少依赖于E6羧基末端区域的精确序列限制,而微小的氨基酸变异对PDZ的识别有重大影响。这些结果表明,E6磷酸化状态在生命周期或恶性进展过程中的变化将调节E6相互作用,并可能反向调节PDZ和14-3-3蛋白的水平。
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来源期刊
Tumour Virus Research
Tumour Virus Research Medicine-Infectious Diseases
CiteScore
6.50
自引率
2.30%
发文量
16
审稿时长
56 days
期刊最新文献
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