Cryo-EM structure of SMG1-SMG8-SMG9 complex. - National Genomics Data Center (CNCB-NGDC)

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Cryo-EM structure of SMG1-SMG8-SMG9 complex.

Li Zhu, Liang Li, Yilun Qi, Zishuo Yu, Yanhui Xu

Author Information

Li Zhu: 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.
Liang Li: 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.
Yilun Qi: 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.
Zishuo Yu: 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.
Yanhui Xu: 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. xuyh@fudan.edu.cn. ORCID

PMID: 31729466 DOI: 10.1038/s41422-019-0255-3

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.

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31830107/National Natural Science Foundation of China (National Science Foundation of China)
31821002/National Natural Science Foundation of China (National Science Foundation of China)

Cryoelectron Microscopy

Humans

Intracellular Signaling Peptides and Proteins

Models, Molecular

Nonsense Mediated mRNA Decay

Phosphorylation

Protein Binding

Protein Conformation

Protein Kinases

Protein Serine-Threonine Kinases

RNA Helicases

Trans-Activators

Intracellular Signaling Peptides and Proteins

SMG8 protein, human

SMG9 protein, human

Trans-Activators

Protein Kinases

Protein Serine-Threonine Kinases

SMG1 protein, human

RNA Helicases

UPF1 protein, human

Journal Article

InsP binding to PIKK kinases revealed by the cryo-EM structure of an SMG1-SMG8-SMG9 complex.Cryo-EM reconstructions of inhibitor-bound SMG1 kinase reveal an autoinhibitory state dependent on SMG8.SMG8/SMG9 Heterodimer Loss Modulates SMG1 Kinase to Drive ATR Inhibitor Resistance.Structure of a SMG8-SMG9 complex identifies a G-domain heterodimer in the NMD effector proteins.Cryo-EM structure of human SRCAP complex.Cryo-EM structure of respiratory complex IV.Cryo-EM structure of the exocyst complex.Cryo-EM structure of the SEA complex.Cryo-EM structure of the bifunctional secretin complex of .Cryo-EM structure of an essential Plasmodium vivax invasion complex.

Identification of a novel compound heterozygous SMG9 variants in a Chinese family with heart and brain malformation syndrome using whole exome sequencing.Recessive, Deleterious Variants in SMG8 Expand the Role of Nonsense-Mediated Decay in Developmental Disorders in Humans.Protein model refinement for cryo-EM maps using AlphaFold2 and the DAQ score.Regulation of RUVBL1-RUVBL2 AAA-ATPases by the nonsense-mediated mRNA decay factor DHX34, as evidenced by Cryo-EM.SMG9 Serves as an Oncogene to Promote the Tumor Progression EMT and Wnt/β-Catenin Signaling Pathway in Hepatocellular Carcinoma.Cryo-EM reconstructions of inhibitor-bound SMG1 kinase reveal an autoinhibitory state dependent on SMG8.Structure of substrate-bound SMG1-8-9 kinase complex reveals molecular basis for phosphorylation specificity.Deciphering the causal association and underlying transcriptional mechanisms between telomere length and abdominal aortic aneurysm.Participation of ATM, SMG1, and DDX5 in a DNA Damage-Induced Alternative Splicing Pathway.The genetic architecture of phenotypic diversity in the Betta fish ().

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