Volume 29, No 12, Dec 2019
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 29 Issue 12, December 2019: 1027-1034
ORIGINAL ARTICLES
Cryo-EM structure of SMG1–SMG8–SMG9 complex
Li Zhu1, Liang Li1, Yilun Qi1, Zishuo Yu1 and Yanhui Xu 1,2,3,4
1 Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Key Laboratory of Medical Epigenetics and Metabolism, Shanghai Medical College of Fudan University, Shanghai 200032, China; 2Key Laboratory of Molecular Medicine, Ministry of Education, Department of Systems Biology for Medicine, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China; 3Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China and 4CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
Correspondence: Yanhui Xu (xuyh@fudan.edu.cn)These authors contributed equally: Li Zhu, Liang Li, Yilun Q
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.
https://doi.org/10.1038/s41422-019-0255-3
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