形态动力学,RNA结合和相分离调节狂犬病病毒P蛋白的多功能性
Stephen M Rawlinson1, Shatabdi Chakraborty2,3, Ashish Sethi2,3,4
1Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia. stephen.rawlinson@monash.edu.
Nature communications
|November 5, 2025
概括
狂犬病病毒P蛋白异型,P1和P3,表现出不同的结构和功能. 在P3的 conformational 变化调节液-液相分离 (LLPS) 和RNA结合,影响病毒复制.
科学领域:
- 病毒学 病毒学
- 分子生物学分子生物学
- 结构生物学 结构生物学
背景情况:
- RNA病毒利用多功能蛋白来管理有限的基因组,影响病毒复制和宿主相互作用.
- 狂犬病病毒P基因产生P1和P3异型,其中P3表现出独特的功能,例如通过液液相分离 (LLPS) 与无膜有机体 (MLOs) 相互作用.
- 蛋白质异形多功能性可能源于涉及内在无序区域 (IDR) 和球状域的结构调节.
研究的目的:
- 研究狂犬病病毒P1和P3蛋白质异型之间的结构和功能差异.
- 阐明P3异型中观察到的功能的增益背后的机制,特别是其与MLO和RNA的相互作用.
- 了解形态调节如何对病毒复制和宿主调制中的异形特异性功能作出贡献.
主要方法:
- 对P1和P3蛋白质结构和功能的比较分析.
- 确定IDRs与C端域之间的异形特异性原原体内相互作用.
- 评估影响MLO相互作用的突变及其对蛋白质构成和RNA结合的影响.
主要成果:
- 确定了IDRs和C端域之间的异形特异性长距离相互作用,与不同的构造状态,LLPS行为和亚细胞局部化相关.
- 改变P3的MLO相互作用的突变也调节了这些长距离的原体内相互作用.
- 虽然这两种异构体都与MLO相关蛋白相互作用,并表现出类似的LLPS能力,但只有P3结合RNA,这种结合与功能增益/丧失突变有关.
结论:
- P1和P3异型之间的形状差异对于调节LLPS行为和蛋白质-RNA相互作用至关重要.
- 这些形状动态控制宿主LLPS结构的可访问性,代表了P蛋白多功能性的新策略.
- 这项研究揭示了以前未知的病毒蛋白功能的机制,通过异构体特定的构造调节和与宿主相隔离区的相互作用.
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