SRSF1 RRM1 结合 RNA 的结构揭示了一种意想不到的双模态相互作用模式，并解释了其在 SMN1 外显子 7 剪接中的参与。
Structure of SRSF1 RRM1 bound to RNA reveals an unexpected bimodal mode of interaction and explains its involvement in SMN1 exon7 splicing.
机构信息
Department of Biology, Institute of Biochemistry, ETH Zurich, Zurich, Switzerland.
Biomolecular NMR Spectroscopy Platform, ETH Zurich, Zurich, Switzerland.
出版信息
Nat Commun. 2021 Jan 18;12(1):428. doi: 10.1038/s41467-020-20481-w.
The human prototypical SR protein SRSF1 is an oncoprotein that contains two RRMs and plays a pivotal role in RNA metabolism. We determined the structure of the RRM1 bound to RNA and found that the domain binds preferentially to a CN motif (N is for any nucleotide). Based on this solution structure, we engineered a protein containing a single glutamate to asparagine mutation (E87N), which gains the ability to bind to uridines and thereby activates SMN exon7 inclusion, a strategy that is used to cure spinal muscular atrophy. Finally, we revealed that the flexible inter-RRM linker of SRSF1 allows RRM1 to bind RNA on both sides of RRM2 binding site. Besides revealing an unexpected bimodal mode of interaction of SRSF1 with RNA, which will be of interest to design new therapeutic strategies, this study brings a new perspective on the mode of action of SRSF1 in cells.
人类原型 SR 蛋白 SRSF1 是一种癌蛋白，它含有两个 RRM 结构域，在 RNA 代谢中发挥关键作用。我们确定了与 RNA 结合的 RRM1 结构域的结构，并发现该结构域优先与 CN 基序（N 代表任何核苷酸）结合。基于这个溶液结构，我们设计了一种含有单个谷氨酸到天冬氨酸突变（E87N）的蛋白质，该突变获得了与尿嘧啶结合的能力，从而激活了 SMN 外显子 7 的包含，这是一种用于治疗脊髓性肌萎缩症的策略。最后，我们揭示了 SRSF1 的柔性 RRM 之间的接头允许 RRM1 在 RRM2 结合位点的两侧结合 RNA。除了揭示 SRSF1 与 RNA 相互作用的一种意外的双峰模式，这将有助于设计新的治疗策略外，这项研究还为 SRSF1 在细胞中的作用模式提供了新的视角。
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