Eukaryotes possess eight highly conserved Lsm (like Sm) proteins that assemble into circular, heteroheptameric complexes, bind RNA, and direct a diverse range of biological processes. Among the many essential functions of Lsm proteins, the cytoplasmic Lsm1-7 complex initiates mRNA decay, while the nuclear Lsm2-8 complex acts as a chaperone for U6 spliceosomal RNA. It has been unclear how these complexes perform their distinct functions while differing by only one out of seven subunits. Here, we elucidate the molecular basis for Lsm-RNA recognition and present four high-resolution structures of Lsm complexes bound to RNAs. The structures of Lsm2-8 bound to RNA identify the unique 2',3' cyclic phosphate end of U6 as a prime determinant of specificity. In contrast, the Lsm1-7 complex strongly discriminates against cyclic phosphates and tightly binds to oligouridylate tracts with terminal purines. Lsm5 uniquely recognizes purine bases, explaining its divergent sequence relative to other Lsm subunits. Lsm1-7 loads onto RNA from the 3' end and removal of the Lsm1 C-terminal region allows Lsm1-7 to scan along RNA, suggesting a gated mechanism for accessing internal binding sites. These data reveal the molecular basis for RNA binding by Lsm proteins, a fundamental step in the formation of molecular assemblies that are central to eukaryotic mRNA metabolism.

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Lsm1-7 和 Lsm2-8 复合物不同细胞功能的分子基础

真核生物拥有八种高度保守的 Lsm（如 Sm）蛋白，它们组装成环状的异七聚体复合物、结合 RNA 并指导各种生物过程。在 Lsm 蛋白的许多基本功能中，细胞质 Lsm1-7 复合物启动 mRNA 衰变，而核 Lsm2-8 复合物充当 U6 剪接体 RNA 的伴侣。目前尚不清楚这些复合物如何执行其独特的功能，而仅在七个亚基中存在一个差异。在这里，我们阐明了 Lsm-RNA 识别的分子基础，并展示了与 RNA 结合的 Lsm 复合物的四种高分辨率结构。Lsm2-8 与 RNA 结合的结构将 U6 独特的 2',3' 环状磷酸末端识别为特异性的主要决定因素。相比之下，Lsm1-7 复合物强烈区分环状磷酸酯，并与具有末端嘌呤的寡尿苷酸束紧密结合。Lsm5 唯一识别嘌呤碱基，解释了其相对于其他 Lsm 亚基的不同序列。Lsm1-7 从 3' 端加载到 RNA 上，去除 Lsm1 C 端区域允许 Lsm1-7 沿 RNA 扫描，这表明访问内部结合位点的门控机制。这些数据揭示了 Lsm 蛋白结合 RNA 的分子基础，这是形成对真核 mRNA 代谢至关重要的分子组装体的基本步骤。Lsm1 C 端区域的末端和去除允许 Lsm1-7 沿 RNA 扫描，表明访问内部结合位点的门控机制。这些数据揭示了 Lsm 蛋白结合 RNA 的分子基础，这是形成对真核 mRNA 代谢至关重要的分子组装体的基本步骤。Lsm1 C 端区域的末端和去除允许 Lsm1-7 沿 RNA 扫描，表明访问内部结合位点的门控机制。这些数据揭示了 Lsm 蛋白结合 RNA 的分子基础，这是形成对真核 mRNA 代谢至关重要的分子组装体的基本步骤。