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Chrustowicz, J.* ; Sherpa, D.* ; Teyra, J.* ; Loke, M.S.* ; Popowicz, G.M. ; Basquin, J.* ; Sattler, M. ; Prabu, J.R.* ; Sidhu, S.S.* ; Schulman, B.A.*

Multifaceted N-degron recognition and ubiquitylation by GID/CTLH E3 ligases.

J. Mol. Biol. 434:167347 (2022)
Publ. Version/Full Text Research data DOI PMC
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N-degron E3 ubiquitin ligases recognize specific residues at the N-termini of substrates. Although molecular details of N-degron recognition are known for several E3 ligases, the range of N-terminal motifs that can bind a given E3 substrate binding domain remains unclear. Here, we discovered capacity of Gid4 and Gid10 substrate receptor subunits of yeast “GID”/human “CTLH” multiprotein E3 ligases to tightly bind a wide range of N-terminal residues whose recognition is determined in part by the downstream sequence context. Screening of phage displaying peptide libraries with exposed N-termini identified novel consensus motifs with non-Pro N-terminal residues binding Gid4 or Gid10 with high affinity. Structural data reveal that conformations of flexible loops in Gid4 and Gid10 complement sequences and folds of interacting peptides. Together with analysis of endogenous substrate degrons, the data show that degron identity, substrate domains harboring targeted lysines, and varying E3 ligase higher-order assemblies combinatorially determine efficiency of ubiquitylation and degradation.
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Publication type Article: Journal article
Document type Scientific Article
Keywords N-degron Pathway ; Phage Display ; Protein–protein Interaction ; Structural Biology ; Ubiquitin; End Rule Pathway; Ubiquitin-proteasome System; Structural Basis; Catabolite Degradation; Terminal Acetylation; Gid Complex; Substrate Recognition; Protein-quality; Molecular-basis; Phage Display
Language english
Publication Year 2022
Prepublished in Year 2021
HGF-reported in Year 2021
ISSN (print) / ISBN 0022-2836
e-ISSN 1089-8638
Journal Journal of Molecular Biology
Quellenangaben Volume: 434, Issue: 2, Pages: , Article Number: 167347 Supplement: ,
Publisher Elsevier
Publishing Place 24-28 Oval Rd, London Nw1 7dx, England
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-503000-001
Grants Deutsche Forschungsgemeinschaft (DFG)
Max Planck Society
Leibniz Prize
DOI 10.1016/j.jmb.2021.167347
WOS ID WOS:000725064200007
Scopus ID 85119584579
PubMed ID 34767800
Erfassungsdatum 2021-12-21
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