{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Clerici M"],"funding":["Swiss National Science Foundation","European Research Council"],"pagination":["2673-86"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC3936715"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["42(4)"],"pubmed_abstract":["Nonsense-mediated decay (NMD) is a eukaryotic quality control pathway, involving conserved proteins UPF1, UPF2 and UPF3b, which detects and degrades mRNAs with premature stop codons. Human UPF2 comprises three tandem MIF4G domains and a C-terminal UPF1 binding region. MIF4G-3 binds UPF3b, but the specific functions of MIF4G-1 and MIF4G-2 are unknown. Crystal structures show that both MIF4G-1 and MIF4G-2 contain N-terminal capping helices essential for stabilization of the 10-helix MIF4G core and that MIF4G-2 interacts with MIF4G-3, forming a rigid assembly. The UPF2/UPF3b/SMG1 complex is thought to activate the kinase SMG1 to phosphorylate UPF1 in vivo. We identify MIF4G-3 as the binding site and in vitro substrate of SMG1 kinase and show that a ternary UPF2 MIF4G-3/UPF3b/SMG1 complex can form in vitro. Whereas in vivo complementation assays show that MIF4G-1 and MIF4G-2 are essential for NMD, tethering assays reveal that UPF2 truncated to only MIF4G-3 and the UPF1-binding region can still partially accomplish NMD. Thus UPF2 MIF4G-1 and MIF4G-2 appear to have a crucial scaffolding role, while MIF4G-3 is the key module required for triggering NMD."],"journal":["Nucleic acids research"],"pubmed_title":["Structural and functional analysis of the three MIF4G domains of nonsense-mediated decay factor UPF2."],"pmcid":["PMC3936715"],"funding_grant_id":["136254","281331"],"pubmed_authors":["Cusack S","Boehm V","Deniaud A","Gehring NH","Clerici M","Schaffitzel C"],"additional_accession":[]},"is_claimable":false,"name":"Structural and functional analysis of the three MIF4G domains of nonsense-mediated decay factor UPF2.","description":"Nonsense-mediated decay (NMD) is a eukaryotic quality control pathway, involving conserved proteins UPF1, UPF2 and UPF3b, which detects and degrades mRNAs with premature stop codons. Human UPF2 comprises three tandem MIF4G domains and a C-terminal UPF1 binding region. MIF4G-3 binds UPF3b, but the specific functions of MIF4G-1 and MIF4G-2 are unknown. Crystal structures show that both MIF4G-1 and MIF4G-2 contain N-terminal capping helices essential for stabilization of the 10-helix MIF4G core and that MIF4G-2 interacts with MIF4G-3, forming a rigid assembly. The UPF2/UPF3b/SMG1 complex is thought to activate the kinase SMG1 to phosphorylate UPF1 in vivo. We identify MIF4G-3 as the binding site and in vitro substrate of SMG1 kinase and show that a ternary UPF2 MIF4G-3/UPF3b/SMG1 complex can form in vitro. Whereas in vivo complementation assays show that MIF4G-1 and MIF4G-2 are essential for NMD, tethering assays reveal that UPF2 truncated to only MIF4G-3 and the UPF1-binding region can still partially accomplish NMD. Thus UPF2 MIF4G-1 and MIF4G-2 appear to have a crucial scaffolding role, while MIF4G-3 is the key module required for triggering NMD.","dates":{"release":"2014-01-01T00:00:00Z","publication":"2014 Feb","modification":"2024-10-18T00:49:45.865Z","creation":"2019-03-27T01:22:25Z"},"accession":"S-EPMC3936715","cross_references":{"pubmed":["24271394"],"doi":["10.1093/nar/gkt1197"]}}