Kinetic analysis of multistep USP7 mechanism shows critical role for target protein in activity

R, Kim; Geurink, Paul P.; Mulder, Monique P. C.; Fish, Alexander; Ekkebus, Reggy; Oualid, Farid El; Dijk, Willem J. van; Dalen, Duco van; Ovaa, Huib; Ingen, Hugo van; Sixma, Titia K.

doi:10.1038/s41467-018-08231-5

Cited by 30 publications

(40 citation statements)

References 64 publications

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“…Without UBL 4–5, the catalytic activity of USP7 is severely compromised. Therefore, a functional full-length USP7 is required for its proper activity ( Faesen et al, 2011a ; Rouge et al, 2016 ; Kim et al, 2019 ).…”

Section: Overview Of Usp7 Structurementioning

confidence: 99%

“…UBL 4–5 has also been speculated to contain a secondary binding site outside of the TRAF-like domain for binding to p53 and Mdm2, although further validation of this site is still needed ( Ma et al, 2010 ; Kim et al, 2019 ).…”

Section: Overview Of Usp7 Structurementioning

confidence: 99%

“…The C-terminal tail of ubiquitin conjugated to a lysine residue of the substrate enters this cleft, allowing for hydrolysis of the isopeptide bond between ubiquitin and the substrate (Hu et al, 2001;Pozhidaeva et al, 2017). Once cleaved, the low affinity between free ubiquitin and the catalytic domain results in subsequent release of the product (Faesen et al, 2011b;Pozhidaeva et al, 2017;Kim et al, 2019). Accordingly, mutations that enhance ubiquitin affinity to USPs result in inhibition of the enzyme (Morrow et al, 2018) Crystal structures of the USP7 catalytic domain apo-enzyme (PDB ID: 1nb8) and the USP7 catalytic domain in complex with ubiquitin-aldehyde (PBD ID: 1nbf), reveal that for the most part, ubiquitin-binding does not result in broad conformational changes to the catalytic domain.…”

Section: Usp7 Catalytic Domainmentioning

confidence: 99%

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USP7 Is a Master Regulator of Genome Stability

Valles

Bezsonova

Woodgate

et al. 2020

Front. Cell Dev. Biol.

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Genetic alterations, including DNA mutations and chromosomal abnormalities, are primary drivers of tumor formation and cancer progression. These alterations can endow cells with a selective growth advantage, enabling cancers to evade cell death, proliferation limits, and immune checkpoints, to metastasize throughout the body. Genetic alterations occur due to failures of the genome stability pathways. In many cancers, the rate of alteration is further accelerated by the deregulation of these processes. The deubiquitinating enzyme ubiquitin specific protease 7 (USP7) has recently emerged as a key regulator of ubiquitination in the genome stability pathways. USP7 is also deregulated in many cancer types, where deviances in USP7 protein levels are correlated with cancer progression. In this work, we review the increasingly evident role of USP7 in maintaining genome stability, the links between USP7 deregulation and cancer progression, as well as the rationale of targeting USP7 in cancer therapy.

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Section: Overview Of Usp7 Structurementioning

confidence: 99%

Section: Overview Of Usp7 Structurementioning

confidence: 99%

Section: Usp7 Catalytic Domainmentioning

confidence: 99%

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USP7 Is a Master Regulator of Genome Stability

Valles

Bezsonova

Woodgate

et al. 2020

Front. Cell Dev. Biol.

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“…There are several levels of USP7 regulation including intramolecular mechanisms, post-transcriptional modifications, and protein-protein interactions. Intramolecular mechanisms include domain reorganization required for the enzyme activation and active site rearrangement (58)(59)(60)(61)(62)(63)(64). Posttranscriptional modifications can further tune the activity of USP7.…”

Section: Regulation Of Usp7 In the Cellmentioning

confidence: 99%

USP7: Structure, substrate specificity, and inhibition

2019

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Turnover of cellular proteins is regulated by Ubiquitin Proteasome System (UPS). Components of this pathway, including the proteasome, ubiquitinating enzymes and deubiquitinating enzymes, are highly specialized and tightly regulated. In this mini-review we focus on the de-ubiquitinating enzyme USP7, and summarize latest advances in understanding its structure, substrate specificity and relevance to human cancers. There is increasing interest in UPS components as targets for cancer therapy and here we also overview the recent progress in the development of small molecule inhibitors that target USP7.

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“…This activation is critically controlled by monoubiquitylation of ASXL proteins [ 114 ]. In a different example, USP7, a DUB with pivotal roles in stem cell self-renewal and differentiation (see below), requires its C-terminal ubiquitin-like domains to fold onto the catalytic USP domain [ 115 , 116 ] resulting in increased intrinsic USP7 activity, which can be further stimulated by binding of an interacting protein in the form of GMP-synthase [ 115 , 117 ]. Similarly, the interaction of UAF1 and WD-repeat-containing proteins with specific DUBs regulates their catalytic activity [ 118 – 120 ].…”

Section: Regulatory Principles Impinging On Dubsmentioning

confidence: 99%

Deubiquitylases in developmental ubiquitin signaling and congenital diseases

2020

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Metazoan development from a one-cell zygote to a fully formed organism requires complex cellular differentiation and communication pathways. To coordinate these processes, embryos frequently encode signaling information with the small protein modifier ubiquitin, which is typically attached to lysine residues within substrates. During ubiquitin signaling, a three-step enzymatic cascade modifies specific substrates with topologically unique ubiquitin modifications, which mediate changes in the substrate’s stability, activity, localization, or interacting proteins. Ubiquitin signaling is critically regulated by deubiquitylases (DUBs), a class of ~100 human enzymes that oppose the conjugation of ubiquitin. DUBs control many essential cellular functions and various aspects of human physiology and development. Recent genetic studies have identified mutations in several DUBs that cause developmental disorders. Here we review principles controlling DUB activity and substrate recruitment that allow these enzymes to regulate ubiquitin signaling during development. We summarize key mechanisms of how DUBs control embryonic and postnatal differentiation processes, highlight developmental disorders that are caused by mutations in particular DUB members, and describe our current understanding of how these mutations disrupt development. Finally, we discuss how emerging tools from human disease genetics will enable the identification and study of novel congenital disease-causing DUBs.

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Kinetic analysis of multistep USP7 mechanism shows critical role for target protein in activity

Cited by 30 publications

References 64 publications

USP7 Is a Master Regulator of Genome Stability

USP7 Is a Master Regulator of Genome Stability

USP7: Structure, substrate specificity, and inhibition

Deubiquitylases in developmental ubiquitin signaling and congenital diseases

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