Abstract：
Latent membrane protein 1 (LMP1) is the primary oncoprotein of Epstein-Barr virus (EBV) and plays versatile roles in the EBV life cycle and pathogenesis. Despite decades of extensive research, the molecular basis for LMP1 folding, assembly, and activation remains unclear. Here, we report cryo-electron microscopy structures of LMP1 in two unexpected assemblies: a symmetric homodimer and a higher-order filamentous oligomer. LMP1 adopts a non-canonical and unpredicted fold that supports the formation of a stable homodimer through tight and antiparallel intermolecular packing. LMP1 dimers further assemble side-by-side into higher-order filamentous oligomers, thereby allowing the accumulation and specific organization of the flexible cytoplasmic tails for efficient recruitment of downstream factors. Super-resolution microscopy and cellular functional assays demonstrate that mutations at both dimeric and oligomeric interfaces disrupt LMP1 higher-order assembly and block multiple LMP1-mediated signaling pathways. Our research provides a framework for understanding the mechanism of LMP1 and for developing potential therapies targeting EBV-associated diseases.
摘要：
潜伏膜蛋白1（LMP1）是EB病毒（EBV）的主要癌蛋白，在EBV的生命周期和发病机理中起着广泛的作用。尽管进行了数十年的广泛研究，LMP1折叠的分子基础，装配,和激活仍不清楚。这里,我们报告了LMP1在两个意外组装中的低温电子显微镜结构：对称同二聚体和高阶丝状低聚物。LMP1采用非规范和未预测的折叠，通过紧密和反平行的分子间堆积支持稳定的同二聚体的形成。LMP1二聚体进一步并排组装成高阶丝状低聚物，从而允许柔性细胞质尾巴的积累和特定组织，以有效募集下游因子。超分辨率显微镜和细胞功能测定表明，二聚体和寡聚界面的突变会破坏LMP1高阶组装并阻断多个LMP1介导的信号传导途径。我们的研究为理解LMP1的机制和开发针对EBV相关疾病的潜在疗法提供了框架。
