Merkel cell polyomavirus (MCV) small T (sT) is the main oncoprotein in Merkel cell carcinoma (MCC) development. A unique domain of sT, LT stabilization domain (LSD), has been reported to bind and inactivate multiple SCF (Skp1-Cullin-F-box) E3 ligases. These interactions impede the turnover of MCV large T (LT) antigen and cellular oncoproteins such as c-Myc and cyclin E, thereby promoting viral replication and cell transformation. However, it is currently unclear how this LSD region contributes to multiple transforming activities of sT. Structural docking simulation of sT and F-box and WD repeat domain-containing 7 (FBW7) revealed a novel allosteric interaction between sT and FBW7 WD40 domain. This model is supported by experimental evidence confirming that charge engineering in the LSD alters sT-WD40 binding. Specifically, loss of net positive charge in the LSD prevents sT-FBW7 binding by abrogating the electrostatic interaction, thus impeding inhibition of FBW7 by sT. Furthermore, positively charged mutations in the LSD significantly restored the sT function and its ability to transform rodent fibroblast cells. We infer that the surface charge of sT is a major determinant for targeting E3 ligases, which leads to sT-induced cell transformation, an observation that could be used to develop targeted therapeutics for MCC.

中文翻译：

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默克尔细胞多瘤病毒小T抗原的表面电荷决定了通过变构FBW7 WD40域靶向的细胞转化。

默克尔细胞多瘤病毒（MCV）小T（sT）是默克尔细胞癌（MCC）发展中的主要癌蛋白。据报道，sT的独特结构域LT稳定结构域（LSD）可以结合并灭活多个SCF（Skp1-Cullin-F-box）E3连接酶。这些相互作用阻碍了MCV大T（LT）抗原和细胞癌蛋白（例如c-Myc和细胞周期蛋白E）的更新，从而促进了病毒复制和细胞转化。然而，目前尚不清楚该LSD区域如何促进sT的多种转化活动。sT和F-box和WD重复域包含7（FBW7）的结构对接模拟揭示了sT和FBW7 WD40域之间的新型变构相互作用。该模型得到实验证据的支持，证实LSD中的电荷工程改变了sT-WD40的结合。特别，LSD中净正电荷的丧失通过消除静电相互作用而阻止了sT-FBW7的结合，从而阻碍了sT对FBW7的抑制。此外，LSD中带正电荷的突变可显着恢复sT功能及其转化啮齿动物成纤维细胞的能力。我们推断，sT的表面电荷是靶向E3连接酶的主要决定因素，它导致sT诱导的细胞转化，这一观察结果可用于开发针对MCC的靶向疗法。