Universität zu Köln

Clerici, Marcello, Deniaud, Aurelien, Boehm, Volker ORCID: 0000-0001-7588-9842, Gehring, Niels H. ORCID: 0000-0001-7792-1164, Schaffitzel, Christiane and Cusack, Stephen ORCID: 0000-0002-9324-0796 (2014). Structural and functional analysis of the three MIF4G domains of nonsense-mediated decay factor UPF2. Nucleic Acids Res., 42 (4). S. 2673 - 2687. OXFORD: OXFORD UNIV PRESS. ISSN 1362-4962

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Clerici, Marcello UNSPECIFIED UNSPECIFIED UNSPECIFIED Deniaud, Aurelien UNSPECIFIED UNSPECIFIED UNSPECIFIED Boehm, Volker UNSPECIFIED orcid.org/0000-0001-7588-9842 UNSPECIFIED Gehring, Niels H. UNSPECIFIED orcid.org/0000-0001-7792-1164 UNSPECIFIED Schaffitzel, Christiane UNSPECIFIED UNSPECIFIED UNSPECIFIED Cusack, Stephen UNSPECIFIED orcid.org/0000-0002-9324-0796 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-447865
DOI:	10.1093/nar/gkt1197
Journal or Publication Title:	Nucleic Acids Res.
Volume:	42
Number:	4
Page Range:	S. 2673 - 2687
Date:	2014
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1362-4962
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MESSENGER-RNA DECAY; EXON-JUNCTION COMPLEX; CRYSTAL-STRUCTURE; SURVEILLANCE COMPLEX; QUALITY-CONTROL; PROTEIN-KINASE; NMD FACTORS; TRANSLATION; BINDING; COMPONENTS Multiple languages Biochemistry & Molecular Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/44786