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.
Highlights
Nonsense-mediated mRNA decay (NMD) is a eukaryotic surveillance mechanism that degrades aberrant mRNAs containing premature translation termination codons (PTCs) (Popp and Maquat 2013; Lykke-Andersen and Bennett 2014; Karousis et al 2016)
Using bioinformatics analyses and proteolysis experiments, we identified regions C. elegans (C.e.) full-length SMG8 (873 residues) and SMG9 (385 residues) as sufficient to form a stable heterodimeric core complex (SMG8c, residues 1–423 and SMG9c, residues 59–375, Fig. 1A) and to yield
The major structural difference between SMG8c and SMG9c is the presence in the former of a helical bundle of three C-terminal helices (α7–α9) that forms a stalk-like protrusion reminiscent of the stalk domain found in GTPases of the dynamin family, such as Atlastin and GBP1 (Fig. 1B; Supplemental Fig. S1; Daumke and Praefcke 2016)
Summary
Nonsense-mediated mRNA decay (NMD) is a eukaryotic surveillance mechanism that degrades aberrant mRNAs containing premature translation termination codons (PTCs) (Popp and Maquat 2013; Lykke-Andersen and Bennett 2014; Karousis et al 2016). Human and nematode SMG8 and SMG9 proteins affect the stability of PTC-containing mRNAs in NMD reporter assays (Yamashita et al 2009). Many of the hydrophobic interface residues observed in the C. elegans SMG8c–SMG9c structure are conserved in the human orthologs
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