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Cited by 109Ubiquitin and proteasome pathwaysEnzyme Structure and FunctionProtein Degradation and Inhibitors

Molecular understanding of USP7 substrate recognition and c-terminal activation.

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Rougé, Lionel, Bainbridge, Travis W., Kwok, Michael, Tong, Raymond, Di Lello, Paola, Wertz, Ingrid E., Maurer, Till, Ernst, James A. +1 more·2016·Structure
DOI 10.1016/j.str.2016.05.020
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Abstract

The deubiquitinating enzyme USP7 has a pivotal role in regulating the stability of proteins involved in fundamental cellular processes of normal biology and disease. Despite the importance of USP7, the mechanisms underlying substrate recognition and catalytic activation are poorly understood. Here we present structural, biochemical, and biophysical analyses elucidating the molecular mechanism by which the C-terminal 19 amino acids of USP7 (residues 1084-1102) enhance the ubiquitin cleavage activity of the deubiquitinase (DUB) domain. Our data demonstrate that the C-terminal peptide binds the activation cleft in the catalytic domain and stabilizes the catalytically competent conformation of USP7. Additional structures of longer fragments of USP7, as well as solution studies, provide insight into full-length USP7, the role of the UBL domains, and demonstrate that both substrate recognition and deubiquitinase activity are highly regulated by the catalytic and noncatalytic domains of USP7, a feature that could be essential for the proper function of multi-domain DUBs.

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  • Following ubiquitin binding to the catalytic domain, the USP7 C-terminal domains assume a conformation that allows its disordered tail (residues 1084-1102) to bind to the switching loop, promoting an active state and increasing USP7 enzymatic activity.

    “Studies have shown that following ubiquitin binding to the catalytic domain, the USP7 C-terminal domains assume a conformation that allows its disordered tail (residues 1084–1102) to bind to the “switching loop.” This conformational switch promotes an “active” state, increasing USP7 enzymatic activity.”

    From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Rouge et al., 2016

  • Efficient enzymatic activity of USP7 requires its UBL 4-5 domains (amino acids 894-1102).

    “Interestingly, efficient enzymatic activity of USP7 requires its UBL 4-5 domains (amino acids 894–1102).”

    From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Rouge et al., 2016

  • A functional full-length USP7 is required for its proper activity.

    “Therefore, a functional full-length USP7 is required for its proper activity (Faesen et al., 2011a; Rouge et al., 2016; Kim et al., 2019).”

    From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Rouge et al., 2016

  • Without UBL 4-5, the catalytic activity of USP7 is severely compromised.

    “Without UBL 4–5, the catalytic activity of USP7 is severely compromised.”

    From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Rouge et al., 2016

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Authors
Rougé, L., Bainbridge, T. W., Kwok, M., Tong, R., Di Lello, P., Wertz, I. E., Maurer, T., Ernst, J. A., & Murray, J.
Affiliations
Genentech (US)
Corresponding author
  • Ernst, James A.
  • Murray, Jeremy
ORCID
Venue
Structure
Publisher
Elsevier BV
Published
2016-08
Volume
24
Issue
8
Pages
1335-1345
ISSN
0969-2126 (ISSN-L)
DOI
10.1016/j.str.2016.05.020
OpenAlex
W2501186188
Cited by
108
References
48
Citations by year
2026: 11 · 2025: 22 · 2024: 9 · 2023: 8 · 2022: 13 · 2021: 7 · 2020: 12 · 2019: 13 · 2018: 4 · 2017: 7 · 2016: 2
FWCI
4.68
Type
journal article
Language
en
Open access
Licence
Locations
  • Structure (publishedVersion)
  • PubMed (publishedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
Funders
US Department of Energy (DE-AC02-05CH11231)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Keywords
USP7, deubiquitinase, substrate recognition, catalytic activation, UBL domain, protein stability, protein conformational stabilization
MeSH terms
Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Ubiquitin-Specific Peptidase 7, Amino Acid Sequence, Cloning, Molecular, Escherichia coli, Humans, Kinetics, Models, Molecular, Protein Binding, Recombinant Proteins, Substrate Specificity, Thermodynamics, Gene Expression, Sequence Alignment, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Crystallography, X-Ray, Catalytic Domain, Ubiquitin, Ubiquitin Thiolesterase, Protein Interaction Domains and Motifs

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