4CEM

Crystal structure of the first MIF4G domain of human nonsense mediated decay factor UPF2

Summary for 4CEM

• Entry DOI: 10.2210/pdb4cem/pdb
• Related: 4CEK
• Descriptor: REGULATOR OF NONSENSE TRANSCRIPTS 2 (2 entities in total)
• Functional Keywords: transcription
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm, perinuclear region: Q9HAU5
• Total number of polymer chains: 2
• Total formula weight: 85931.73

Authors

Clerici, M.,Deniaud, A.,Boehm, V.,Gehring, N.H.,Schaffitzel, C.,Cusack, S. (deposition date: 2013-11-11, release date: 2013-12-11, Last modification date: 2024-10-16)

Primary citation

Clerici, M.,Deniaud, A.,Boehm, V.,Gehring, N.H.,Schaffitzel, C.,Cusack, S.
Structural and Functional Analysis of the Three Mif4G Domains of Nonsense-Mediated Decay Factor Upf2.
Nucleic Acids Res., 42:2673-, 2014

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.

PubMed: 24271394
DOI: 10.1093/NAR/GKT1197

Experimental method

X-RAY DIFFRACTION (2.6 Å)