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Structure of a SMG8-SMG9 complex identifies a G-domain heterodimer in the NMD effector proteins
Liang Li1, Mahesh Lingaraju1, Claire Basquin1
1Department of Structural Cell Biology, Max-Planck-Institute of Biochemistry, D-82152 Martinsried, Germany.
Abstract:
Nonsense-mediated mRNA decay (NMD) is a eukaryotic mRNA degradation pathway involved in surveillance and post-transcriptional regulation, and executed by the concerted action of several trans-acting factors. The SMG1 kinase is an essential NMD factor in metazoans and is associated with two recently identified and yet poorly characterized proteins, SMG8 and SMG9. We determined the 2.5 Å resolution crystal structure of a SMG8-SMG9 core complex from C. elegans We found that SMG8-SMG9 is a G-domain heterodimer with architectural similarities to the dynamin-like family of GTPases such as Atlastin and GBP1. The SMG8-SMG9 heterodimer forms in the absence of nucleotides, with interactions conserved from worms to humans. Nucleotide binding occurs at the G domain of SMG9 but not of SMG8. Fitting the GDP-bound SMG8-SMG9 structure in EM densities of the human SMG1-SMG8-SMG9 complex raises the possibility that the nucleotide site of SMG9 faces SMG1 and could impact the kinase conformation and/or regulation.
Insights
The SMG1 kinase complex
Area of Science:
- Molecular Biology
- Structural Biology
- Biochemistry
Background:
- Nonsense-mediated mRNA decay (NMD) is a crucial eukaryotic surveillance pathway.
- SMG1 kinase is essential for NMD, interacting with SMG8 and SMG9 proteins.
- The structure and function of SMG8 and SMG9 are poorly understood.
Purpose of the Study:
- To elucidate the structural basis of the SMG8-SMG9 complex.
- To understand the interaction between SMG1, SMG8, and SMG9 in NMD.
Main Methods:
- X-ray crystallography of the SMG8-SMG9 core complex from C. elegans at 2.5 Å resolution.
- Structural analysis and comparison with dynamin-like GTPases.
- Fitting the GDP-bound SMG8-SMG9 structure into human SMG1-SMG8-SMG9 complex EM densities.
Main Results:
- The SMG8-SMG9 complex forms a nucleotide-free G-domain heterodimer.
- Architectural similarities were found with dynamin-like GTPases (Atlastin, GBP1).
- Nucleotide binding is specific to the G domain of SMG9, not SMG8.
Conclusions:
- SMG8 and SMG9 form a conserved heterodimer crucial for NMD.
- The nucleotide-binding site on SMG9 may interact with SMG1, suggesting a regulatory role.
- This structural insight provides a foundation for understanding SMG1 kinase regulation in NMD.