Format

Send to

Choose Destination
Nucleic Acids Res. 2015 Sep 3;43(15):7600-11. doi: 10.1093/nar/gkv668. Epub 2015 Jun 30.

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

Author information

1
European Molecular Biology Laboratory, Grenoble Outstation, 71 Avenue des Martyrs, 38042 Grenoble, France Unit of Virus Host-Cell Interactions, University Grenoble Alpes-EMBL-CNRS, UMI 3265, 71 Avenue des Martyrs, 38042 Grenoble, France.
2
European Molecular Biology Laboratory, Structural and Computational Biology Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
3
Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany.
4
Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
5
European Molecular Biology Laboratory, Grenoble Outstation, 71 Avenue des Martyrs, 38042 Grenoble, France Unit of Virus Host-Cell Interactions, University Grenoble Alpes-EMBL-CNRS, UMI 3265, 71 Avenue des Martyrs, 38042 Grenoble, France School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK schaffitzel@embl.fr.

Abstract

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.

PMID:
26130714
PMCID:
PMC4551919
DOI:
10.1093/nar/gkv668
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center