Molecular Biophysics Unit, Indian Institute of Science Bangalore, Bangalore, Karnataka, India.
Department of Molecular and Cell Biology, Indian Institute of Science Bangalore, Bangalore, Karnataka, India.
J Biol Chem. 2023 Dec;299(12):105392. doi: 10.1016/j.jbc.2023.105392. Epub 2023 Oct 27.
Fused in sarcoma (FUS) is an abundant RNA-binding protein, which drives phase separation of cellular condensates and plays multiple roles in RNA regulation. The RNA-binding ability of FUS protein is crucial to its cellular function. Here, our molecular simulation study on the FUS-RNA complex provides atomic resolution insights into the observations from biochemical studies and also illuminates our understanding of molecular driving forces that mediate the structure, stability, and interaction of the RNA recognition motif (RRM) and RGG domains of FUS with a stem-loop junction RNA. We observe clear cooperativity and division of labor among the ordered (RRM) and disordered domains (RGG1 and RGG2) of FUS that leads to an organized and tighter RNA binding. Irrespective of the length of RGG2, the RGG2-RNA interaction is confined to the stem-loop junction and the proximal stem regions. On the other hand, the RGG1 interactions are primarily with the longer RNA stem. We find that the C terminus of RRM, which make up the "boundary residues" that connect the folded RRM with the long disordered RGG2 stretch of the protein, plays a critical role in FUS-RNA binding. Our study provides high-resolution molecular insights into the FUS-RNA interactions and forms the basis for understanding the molecular origins of full-length FUS interaction with RNA.
融合肉瘤（FUS）是一种丰富的 RNA 结合蛋白，可驱动细胞凝聚物的相分离，并在 RNA 调节中发挥多种作用。FUS 蛋白的 RNA 结合能力对其细胞功能至关重要。在这里，我们对 FUS-RNA 复合物的分子模拟研究提供了原子分辨率的见解，阐明了我们对介导 RNA 识别基序（RRM）和 RGG 结构域与茎环连接 RNA 相互作用的分子驱动力的理解。我们观察到 FUS 中有序（RRM）和无序域（RGG1 和 RGG2）之间存在明显的协同作用和分工，从而导致有组织的更紧密的 RNA 结合。无论 RGG2 的长度如何，RGG2-RNA 相互作用都局限于茎环连接和近端茎区。另一方面，RGG1 相互作用主要与较长的 RNA 茎结合。我们发现 RRM 的 C 端构成了连接折叠的 RRM 与蛋白质中长的无序 RGG2 延伸的“边界残基”，在 FUS-RNA 结合中起着关键作用。我们的研究提供了 FUS-RNA 相互作用的高分辨率分子见解，并为理解全长 FUS 与 RNA 的相互作用的分子起源奠定了基础。
