Structure of substrate-bound SMG1-8-9 kinase complex reveals molecular basis for phosphorylation specificity
- Max Planck Institute of Biochemistry, Germany
Abstract
PI3K-related kinases (PIKKs) are large Serine/Threonine (Ser/Thr)-protein kinases central to the regulation of many fundamental cellular processes. PIKK family member SMG1 orchestrates progression of an RNA quality control pathway, termed nonsense-mediated mRNA decay (NMD), by phosphorylating the NMD factor UPF1. Phosphorylation of UPF1 occurs in its unstructured N- and C-terminal regions at Serine/Threonine-Glutamine (SQ) motifs. How SMG1 and other PIKKs specifically recognize SQ motifs has remained unclear. Here, we present a cryo-electron microscopy (cryo-EM) reconstruction of a human SMG1-8-9 kinase complex bound to a UPF1 phosphorylation site at an overall resolution of 2.9 Å. This structure provides the first snapshot of a human PIKK with a substrate-bound active site. Together with biochemical assays, it rationalizes how SMG1 and perhaps other PIKKs specifically phosphorylate Ser/Thr-containing motifs with a glutamine residue at position +1 and a hydrophobic residue at position -1, thus elucidating the molecular basis for phosphorylation site recognition.
Data availability
EM data have been deposited in EMDB under the accession code EMD-11063. The model has been deposited in PDB under the accession 6Z3R.
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Structure of SMG1-8-9 kinase complex bound to UPF1-LSQProtein Data Bank, 6Z3R.
Article and author information
Author details
Funding
Boehringer Ingelheim Fonds (PhD fellowship)
- Lukas M Langer
Max-Planck-Gesellschaft
- Elena Conti
European Commission (ERC Advanced Investigator Grant EXORICO)
- Elena Conti
Deutsche Forschungsgemeinschaft (SFB1035,GRK1721,SFB/TRR 237)
- Elena Conti
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Langer et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Structure of substrate-bound SMG1-8-9 kinase complex reveals molecular basis for phosphorylation specificity
eLife 9:e57127.
https://doi.org/10.7554/eLife.57127
