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A network of SMG-8, SMG-9 and SMG-1 C-terminal insertion domain regulates UPF1 substrate recruitment and phosphorylation

Mammalian nonsense-mediated mRNA decay (NMD) is a eukaryotic surveillance mechanism that degrades mRNAs containing premature translation termination codons. Phosphorylation of the essential NMD effector UPF1 by the phosphoinositide-3-kinase-like kinase (PIKK) SMG-1 is a key step in NMD and occurs wh...

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Hauptverfasser: Deniaud, Aurélien (VerfasserIn) , Karuppasamy, Manikandan (VerfasserIn) , Bock, Thomas (VerfasserIn) , Masiulis, Simonas (VerfasserIn) , Huard, Karine (VerfasserIn) , Garzoni, Frédéric (VerfasserIn) , Kerschgens, Kathrin (VerfasserIn) , Hentze, Matthias W. (VerfasserIn) , Kulozik, Andreas (VerfasserIn) , Beck, Martin (VerfasserIn) , Neu-Yilik, Gabriele (VerfasserIn) , Schaffitzel, Christiane (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 30 June 2015
In: Nucleic acids research
Year: 2015, Jahrgang: 43, Heft: 15, Pages: 7600-7611
ISSN:1362-4962
DOI:10.1093/nar/gkv668
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1093/nar/gkv668
Volltext
Verfasserangaben:Aurélien Deniaud, Manikandan Karuppasamy, Thomas Bock, Simonas Masiulis, Karine Huard, Frédéric Garzoni, Kathrin Kerschgens, Matthias W. Hentze, Andreas E. Kulozik, Martin Beck, Gabriele Neu-Yilik and Christiane Schaffitzel
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Zusammenfassung:Mammalian nonsense-mediated mRNA decay (NMD) is a eukaryotic surveillance mechanism that degrades mRNAs containing premature translation termination codons. Phosphorylation of the essential NMD effector UPF1 by the phosphoinositide-3-kinase-like kinase (PIKK) SMG-1 is a key step in NMD and occurs when SMG-1, its two regulatory factors SMG-8 and SMG-9, and UPF1 form a complex at a terminating ribosome. Electron cryo-microscopy of the SMG-1-8-9-UPF1 complex shows the head and arm architecture characteristic of PIKKs and reveals different states of UPF1 docking. UPF1 is recruited to the SMG-1 kinase domain and C-terminal insertion domain, inducing an opening of the head domain that provides access to the active site. SMG-8 and SMG-9 interact with the SMG-1 C-insertion and promote high-affinity UPF1 binding to SMG-1-8-9, as well as decelerated SMG-1 kinase activity and enhanced stringency of phosphorylation site selection. The presence of UPF2 destabilizes the SMG-1-8-9-UPF1 complex leading to substrate release. Our results suggest an intricate molecular network of SMG-8, SMG-9 and the SMG-1 C-insertion domain that governs UPF1 substrate recruitment and phosphorylation by SMG-1 kinase, an event that is central to trigger mRNA decay.
Beschreibung:Gesehen am 12.01.2021
Beschreibung:Online Resource
ISSN:1362-4962
DOI:10.1093/nar/gkv668

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