Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.
Phys Chem Chem Phys. 2023 Mar 22;25(12):8714-8724. doi: 10.1039/d3cp00227f.
Uridine diphosphate glucose (UDP-Glc) is able to accelerate the decay of snail family transcriptional repressor 1 () mRNA by inhibiting Hu antigen R (HuR, an RNA-binding protein), thereby preventing cancer invasiveness and drug resistance. Nevertheless, the phosphorylation of tyrosine 473 (Y473) of UDP-glucose dehydrogenase (UGDH is capable of converting UDP-Glc to uridine diphosphate glucuronic acid (UDP-GlcUA)) weakens the inhibition of UDP-Glc to HuR, thus initiating the epithelial-mesenchymal transformation of tumor cells and promoting tumor cell migration and metastasis. To address the mechanism, we performed molecular dynamics simulations combined with molecular mechanics generalized Born surface area (MM/GBSA) analysis on wild-type and Y473 phosphorylated UGDH and HuR, UDP-Glc, UDP-GlcUA complexes. We demonstrated that Y473 phosphorylation was able to enhance the binding between UGDH and the HuR/UDP-Glc complex. Compared with HuR, UGDH has a stronger binding ability with UDP-Glc; therefore, UDP-Glc was inclined to bind to UGDH and then was catalyzed to UDP-GlcUA by UGDH, which relieved the inhibition of UDP-Glc to HuR. In addition, the binding ability of HuR for UDP-GlcUA was lower than its affinity for UDP-Glc, significantly reducing the inhibition of HuR. Hence, HuR bound to mRNA more easily to increase the stability of mRNA. Our results revealed the micromolecular mechanism of Y473 phosphorylation of UGDH regulating the interaction between UGDH and HuR as well as relieving the inhibition of UDP-Glc on HuR, which contributed to understanding the role of UGDH and HuR in tumor metastasis and developing small molecule drugs targeting the interaction between UGDH and HuR.
尿苷二磷酸葡萄糖（UDP-Glc）能够通过抑制 Hu 抗原 R（一种 RNA 结合蛋白）来加速蜗牛家族转录阻遏物 1()mRNA 的降解，从而防止癌症侵袭和耐药性。然而，UDP-葡萄糖脱氢酶（UGDH，能够将 UDP-Glc 转化为尿苷二磷酸葡萄糖醛酸（UDP-GlcUA））的酪氨酸 473（Y473）磷酸化会削弱 UDP-Glc 对 HuR 的抑制作用，从而启动肿瘤细胞的上皮-间充质转化，促进肿瘤细胞迁移和转移。为了解决这一机制问题，我们对野生型和 Y473 磷酸化 UGDH 以及 HuR、UDP-Glc、UDP-GlcUA 复合物进行了分子动力学模拟和分子力学广义 Born 表面积（MM/GBSA）分析。我们证明了 Y473 磷酸化能够增强 UGDH 与 HuR/UDP-Glc 复合物的结合。与 HuR 相比，UGDH 与 UDP-Glc 的结合能力更强；因此，UDP-Glc 更倾向于与 UGDH 结合，然后被 UGDH 催化为 UDP-GlcUA，从而解除了 UDP-Glc 对 HuR 的抑制作用。此外，HuR 与 UDP-GlcUA 的结合能力低于其与 UDP-Glc 的亲和力，从而显著降低了对 HuR 的抑制作用。因此，HuR 更容易与 mRNA 结合，从而增加了 mRNA 的稳定性。我们的研究结果揭示了 UGDH 的 Y473 磷酸化调节 UGDH 与 HuR 相互作用以及解除 UDP-Glc 对 HuR 抑制作用的微观分子机制，有助于理解 UGDH 和 HuR 在肿瘤转移中的作用，并开发针对 UGDH 和 HuR 相互作用的小分子药物。
