Cited by 612Ubiquitin and proteasome pathwaysWnt/β-catenin signaling in development and cancerEnzyme Structure and Function

Structure of a β-TrCP1-Skp1-β-Catenin Complex

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Wu, Geng, Xu, Guozhou, Schulman, Brenda A., Jeffrey, Philip D., Harper, J.Wade, Pavletich, Nikola P.·2003·Molecular Cell

Abstract

The SCF ubiquitin ligases catalyze protein ubiquitination in diverse cellular processes. SCFs bind substrates through the interchangeable F box protein subunit, with the >70 human F box proteins allowing the recognition of a wide range of substrates. The F box protein beta-TrCP1 recognizes the doubly phosphorylated DpSGphiXpS destruction motif, present in beta-catenin and IkappaB, and directs the SCF(beta-TrCP1) to ubiquitinate these proteins at specific lysines. The 3.0 A structure of a beta-TrCP1-Skp1-beta-catenin complex reveals the basis of substrate recognition by the beta-TrCP1 WD40 domain. The structure, together with the previous SCF(Skp2) structure, leads to the model of SCF catalyzing ubiquitination by increasing the effective concentration of the substrate lysine at the E2 active site. The model's prediction that the lysine-destruction motif spacing is a determinant of ubiquitination efficiency is confirmed by measuring ubiquitination rates of mutant beta-catenin peptides, solidifying the model and also providing a mechanistic basis for lysine selection.

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Crossref · 10.1016/s1097-2765(03)00234-x

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Authors
Wu, G., Xu, G., Schulman, B. A., Jeffrey, P. D., Harper, J. W., & Pavletich, N. P.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
Pavletich, Nikola P.
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2003-06
Volume
11
Issue
6
Pages
1445-1456
ISSN
1097-2765 (ISSN-L)
OpenAlex
W2147291971
Cited by
612
References
41
Citations by year
2026: 19 · 2025: 26 · 2024: 13 · 2023: 18 · 2022: 14 · 2021: 24 · 2020: 30 · 2019: 19 · 2018: 19 · 2017: 20 · 2016: 16 · 2015: 21 · 2014: 37 · 2013: 39 · 2012: 25
FWCI
13.10
Type
journal article
Language
en
Open access
Locations
  • Molecular Cell (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute on Aging (R01AG011085)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
Keywords
β-TrCP1, Skp1, β-catenin, SCF ubiquitin ligase, F-box protein, WD40 domain, substrate recognition, ubiquitination, IκB
MeSH terms
Amino Acid Sequence, Binding Sites, Cytoskeletal Proteins, Humans, Kinetics, Ligases, Lysine, Models, Molecular, Molecular Sequence Data, Peptides, Protein Binding, Protein Conformation, Substrate Specificity, Trans-Activators, Consensus Sequence, Conserved Sequence, Crystallography, X-Ray, Cell Cycle Proteins, GTP-Binding Proteins, Amino Acid Motifs, Ubiquitin, S-Phase Kinase-Associated Proteins, beta-Transducin Repeat-Containing Proteins, beta Catenin

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