Structure of substrate-bound SMG1-8-9 kinase complex reveals molecular basis for phosphorylation specificity
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 NM...
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eLife Sciences Publications Ltd
2020-05-01
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Online Access: | https://elifesciences.org/articles/57127 |
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author | Lukas M Langer Yair Gat Fabien Bonneau Elena Conti |
author_facet | Lukas M Langer Yair Gat Fabien Bonneau Elena Conti |
author_sort | Lukas M Langer |
collection | DOAJ |
description | 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. |
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language | English |
last_indexed | 2024-04-12T02:20:00Z |
publishDate | 2020-05-01 |
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spelling | doaj.art-77c42d6d12404221a6fddbe50a007cf22022-12-22T03:52:09ZengeLife Sciences Publications LtdeLife2050-084X2020-05-01910.7554/eLife.57127Structure of substrate-bound SMG1-8-9 kinase complex reveals molecular basis for phosphorylation specificityLukas M Langer0https://orcid.org/0000-0002-9977-2427Yair Gat1https://orcid.org/0000-0002-2338-9384Fabien Bonneau2https://orcid.org/0000-0001-8787-7662Elena Conti3https://orcid.org/0000-0003-1254-5588Department of Structural Cell Biology, Max Planck Institute of Biochemistry, Martinsried, GermanyDepartment of Structural Cell Biology, Max Planck Institute of Biochemistry, Martinsried, GermanyDepartment of Structural Cell Biology, Max Planck Institute of Biochemistry, Martinsried, GermanyDepartment of Structural Cell Biology, Max Planck Institute of Biochemistry, Martinsried, GermanyPI3K-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.https://elifesciences.org/articles/57127PIKKnonsense-mediated mRNA decayCryo-EMphosphorylationRNA quality control |
spellingShingle | Lukas M Langer Yair Gat Fabien Bonneau Elena Conti Structure of substrate-bound SMG1-8-9 kinase complex reveals molecular basis for phosphorylation specificity eLife PIKK nonsense-mediated mRNA decay Cryo-EM phosphorylation RNA quality control |
title | Structure of substrate-bound SMG1-8-9 kinase complex reveals molecular basis for phosphorylation specificity |
title_full | Structure of substrate-bound SMG1-8-9 kinase complex reveals molecular basis for phosphorylation specificity |
title_fullStr | Structure of substrate-bound SMG1-8-9 kinase complex reveals molecular basis for phosphorylation specificity |
title_full_unstemmed | Structure of substrate-bound SMG1-8-9 kinase complex reveals molecular basis for phosphorylation specificity |
title_short | Structure of substrate-bound SMG1-8-9 kinase complex reveals molecular basis for phosphorylation specificity |
title_sort | structure of substrate bound smg1 8 9 kinase complex reveals molecular basis for phosphorylation specificity |
topic | PIKK nonsense-mediated mRNA decay Cryo-EM phosphorylation RNA quality control |
url | https://elifesciences.org/articles/57127 |
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