Kinetic analysis of multistep USP7 mechanism shows critical role for target protein in activity.
Open accessAbstract
USP7 is a highly abundant deubiquitinating enzyme (DUB), involved in cellular processes including DNA damage response and apoptosis. USP7 has an unusual catalytic mechanism, where the low intrinsic activity of the catalytic domain (CD) increases when the C-terminal Ubl domains (Ubl45) fold onto the CD, allowing binding of the activating C-terminal tail near the catalytic site. Here we delineate how the target protein promotes the activation of USP7. Using NMR analysis and biochemistry we describe the order of activation steps, showing that ubiquitin binding is an instrumental step in USP7 activation. Using chemically synthesised p53-peptides we also demonstrate how the correct ubiquitinated substrate increases catalytic activity. We then used transient reaction kinetic modelling to define how the USP7 multistep mechanism is driven by target recognition. Our data show how this pleiotropic DUB can gain specificity for its cellular targets.
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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 Kim et al., 2019
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 Kim et al., 2019
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 Kim et al., 2019
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 Kim et al., 2019
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USP7: Structure, substrate specificity, and inhibition
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“USP7 UBLs function as di-UBL units in a 2-1-2 domain architecture: UBL 1-2, UBL 3, and UBL 4-5 (Kim and Sixma, 2017).”
BackgroundThe small CRL4CSA ubiquitin ligase component DDA1 regulates transcription-coupled repair dynamics
Llerena Schiffmacher, D. A., Lee, S.-H., Kliza, K. W., Theil, A. F., Akita, M., Helfricht, A., Bezstarosti, K., Gonzalo-Hansen, C., van Attikum, H., Verlaan-de Vries, M., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-50584-7 · Cited by 19 · see citing works
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- Authors
- Kim, R. Q., Geurink, P. P., Mulder, M. P. C., Fish, A., Ekkebus, R., El Oualid, F., van Dijk, W. J., van Dalen, D., Ovaa, H., van Ingen, H., & Sixma, T. K.
- Affiliations
- The Netherlands Cancer Institute (NL)
- Leiden University Medical Center (NL)
- Corresponding author
- Ovaa, Huib
- Sixma, Titia K.
- Venue
- Nature Communications
- Published
- 2019-01-16
- Volume
- 10
- Issue
- 1
- Pages
- 231-231
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6335408
- OpenAlex
- W2909882222
- Cited by
- 41
- References
- 67
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 5 · 2023: 8 · 2022: 4 · 2021: 4 · 2020: 4 · 2019: 3
- FWCI
- 1.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (724.013.002, 714.016.002, 723.013.010)
- Oncode Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- USP7, deubiquitinase, catalytic mechanism, UBL domain, ubiquitin binding, enzyme activation, p53, substrate specificity, reaction kinetics, DNA damage response, apoptosis
- MeSH terms
- Ubiquitin-Specific Peptidase 7, Carbon Isotopes, Kinetics, Models, Chemical, Nitrogen Isotopes, Peptides, Protein Binding, Protein Processing, Post-Translational, Recombinant Proteins, Substrate Specificity, Tumor Suppressor Protein p53, Mutagenesis, Site-Directed, Nuclear Magnetic Resonance, Biomolecular, Catalytic Domain, Surface Plasmon Resonance, Ubiquitin, Enzyme Assays
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