Nonsense-mediated mRNA decay (NMD) targets premature stop codon (PTC)-containing mRNAs for rapid degradation, and is essential for mammalian embryonic development, brain development and modulation of the stress response. The key event in NMD is the SMG1-mediated phosphorylation of an RNA helicase UPF1 and SMG1 kinase activity is inhibited by SMG8 and SMG9 in an unknown mechanism. Here, we determined the cryo-EM structures of human SMG1 at 3.6 Å resolution and the SMG1-SMG8-SMG9 complex at 3.4 Å resolution, respectively. SMG8 has a C-terminal kinase inhibitory domain (KID), which covers the catalytic pocket and inhibits the kinase activity of SMG1. Structural analyses suggest that GTP hydrolysis of SMG9 would lead to a dramatic conformational change of SMG8-SMG9 and the KID would move away from the inhibitory position to restore SMG1 kinase activity. Thus, our structural and biochemical analyses provide a mechanistic understanding of SMG1-SMG8-SMG9 complex assembly and the regulatory mechanism of SMG1 kinase activity.

中文翻译：

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SMG1-SMG8-SMG9 复合物的冷冻电镜结构。

无义介导的 mRNA 衰变 (NMD) 以含有提前终止密码子 (PTC) 的 mRNA 为目标进行快速降解，这对于哺乳动物胚胎发育、大脑发育和应激反应的调节至关重要。NMD 中的关键事件是 SMG1 介导的 RNA 解旋酶 UPF1 磷酸化，SMG1 激酶活性被 SMG8 和 SMG9 以未知机制抑制。在这里，我们分别以 3.6 Å 的分辨率测定了人类 SMG1 的冷冻电镜结构和分辨率为 3.4 Å 的 SMG1-SMG8-SMG9 复合物。SMG8 有一个 C 末端激酶抑制结构域 (KID)，它覆盖催化口袋并抑制 SMG1 的激酶活性。结构分析表明 SMG9 的 GTP 水解会导致 SMG8-SMG9 的构象发生显着变化，并且 KID 将远离抑制位置以恢复 SMG1 激酶活性。因此，我们的结构和生化分析提供了对 SMG1-SMG8-SMG9 复合物组装和 SMG1 激酶活性调节机制的机械理解。