Journal
NUCLEIC ACIDS RESEARCH
Volume 43, Issue 15, Pages 7600-7611Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkv668
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Funding
- EC FP7 I3 project P-CUBE
- EC-EMBL CoFUNDS EI-POD fellowship
- European Research Council Starting grant (ComplexNMD) [281331]
- Sinergia grant from the Swiss National Science Foundation [CRSII3_136254 /1]
- European Research Council (ERC) [281331] Funding Source: European Research Council (ERC)
- Swiss National Science Foundation (SNF) [CRSII3_136254] Funding Source: Swiss National Science Foundation (SNF)
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Mammalian nonsense-mediated mRNA decay (NMD) is a eukaryotic surveillance mechanism that degrades mRNAs containing premature translation termination codons. Phosphorylation of the essential NMD effector UPF1 by the phosphoinositide-3-kinase-like kinase (PIKK) SMG-1 is a key step in NMD and occurs when SMG-1, its two regulatory factors SMG-8 and SMG-9, and UPF1 form a complex at a terminating ribosome. Electron cryo-microscopy of the SMG-1-8-9-UPF1 complex shows the head and arm architecture characteristic of PIKKs and reveals different states of UPF1 docking. UPF1 is recruited to the SMG-1 kinase domain and C-terminal insertion domain, inducing an opening of the head domain that provides access to the active site. SMG-8 and SMG-9 interact with the SMG-1 C-insertion and promote high-affinity UPF1 binding to SMG-1-8-9, as well as decelerated SMG-1 kinase activity and enhanced stringency of phosphorylation site selection. The presence of UPF2 destabilizes the SMG-1-8-9-UPF1 complex leading to substrate release. Our results suggest an intricate molecular network of SMG-8, SMG-9 and the SMG-1 C-insertion domain that governs UPF1 substrate recruitment and phosphorylation by SMG-1 kinase, an event that is central to trigger mRNA decay.
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