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The cryo-EM structure of the UPF–EJC complex shows UPF1 poised toward the RNA 3′ end

2012; Nature Portfolio; Volume: 19; Issue: 5 Linguagem: Inglês

10.1038/nsmb.2287

1545-9993

Roberto Melero, Gretel Buchwald, Raquel Castaño, Monika Raabe, David Gil-Cartón, Melisa Lázaro, Henning Urlaub, Elena Conti, Óscar Llorca,

RNA modifications and cancer

The nonsense-mediated mRNA decay (NMD) pathway is triggered upon assembly of the UPF surveillance complex near an exon junction complex (EJC). Cryo-EM studies have revealed the geometry of this transient assembly between the UPF complex and the EJC, which demonstrates how the UPF1 subunit elicits its RNA helicase activity toward the 3A end of the mRNA. Nonsense-mediated mRNA decay (NMD) is a eukaryotic surveillance pathway that degrades aberrant mRNAs containing premature termination codons (PTCs). NMD is triggered upon the assembly of the UPF surveillance complex near a PTC. In humans, UPF assembly is prompted by the exon junction complex (EJC). We investigated the molecular architecture of the human UPF complex bound to the EJC by cryo-EM and using positional restraints from additional EM, MS and biochemical interaction data. The heptameric assembly is built around UPF2, a scaffold protein with a ring structure that closes around the CH domain of UPF1, keeping the helicase region in an accessible and unwinding-competent state. UPF2 also positions UPF3 to interact with the EJC. The geometry is such that this transient complex poises UPF1 to elicit helicase activity toward the 3′ end of the mRNP.