期刊
EMBO JOURNAL
卷 28, 期 15, 页码 2293-2306出版社
WILEY
DOI: 10.1038/emboj.2009.175
关键词
mRNA quality control; nonsense mediate decay (NMD); NMR; UPF1; UPF2; X-ay crystallography
资金
- Portuguese Foundation for Science and Technology (FCT) [SFRH/BD/22323/2005]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/22323/2005] Funding Source: FCT
Nonsense-mediated decay (NMD) is a eukaryotic quality control mechanism that degrades mRNAs carrying premature stop codons. In mammalian cells, NMD is triggered when UPF2 bound to UPF3 on a downstream exon junction complex interacts with UPF1 bound to a stalled ribosome. We report structural studies on the interaction between the C-terminal region of UPF2 and intact UPF1. Crystal structures, confirmed by EM and SAXS, show that the UPF1 CH-domain is docked onto its helicase domain in a fixed configuration. The C-terminal region of UPF2 is natively unfolded but binds through separated alpha-helical and beta-hairpin elements to the UPF1 CH-domain. The alpha-helical region binds sixfold more weakly than the beta-hairpin, whereas the combined elements bind 80-fold more tightly. Cellular assays show that NMD is severely affected by mutations disrupting the beta-hairpin binding, but not by those only affecting alpha-helix binding. We propose that the bipartite mode of UPF2 binding to UPF1 brings the ribosome and the EJC in close proximity by forming a tight complex after an initial weak encounter with either element. The EMBO Journal (2009) 28, 2293-2306. doi: 10.1038/emboj.2009.175; Published online 25 June 2009
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