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  Structure of substrate-bound SMG1-8-9 kinase complex reveals molecular basis for phosphorylation specificity

Langer, L. M., Gat, Y., Bonneau, F., & Conti, E. (2020). Structure of substrate-bound SMG1-8-9 kinase complex reveals molecular basis for phosphorylation specificity. ELIFE, 9: e57127. doi:10.7554/eLife.57127.

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 Creators:
Langer, Lukas M.1, Author              
Gat, Yair1, Author              
Bonneau, Fabien1, Author              
Conti, Elena1, Author              
Affiliations:
1Conti, Elena / Structural Cell Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565144              

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Free keywords: CRYO-EM STRUCTURE; PIGGYBAC TRANSPOSASE; PROTEIN-KINASE; HUMAN SMG-1; UPF1; VISUALIZATION; ORIENTATION; METABOLISM; MECHANISMS; NETWORK
 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 angstrom. 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(s): eng - English
 Dates: 2020
 Publication Status: Published online
 Pages: 14
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000547377100001
DOI: 10.7554/eLife.57127
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Title: ELIFE
Source Genre: Journal
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Publ. Info: SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND : ELIFE SCIENCES PUBLICATIONS LTD
Pages: - Volume / Issue: 9 Sequence Number: e57127 Start / End Page: - Identifier: ISSN: 2050-084X