Molecular recognition of p53 and MDM2 by USP7/HAUSP

Sheng, Yi; Saridakis, V.; Sarkari, Feroz; Duan, Shili; Wu, Tianne; Arrowsmith, C.H.; Frappier, Lori

doi:10.1038/nsmb1067

Cited by 264 publications

(290 citation statements)

References 17 publications

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“…However, the mode of peptide binding and the adopted conformation of the bound peptide differ significantly from previously observed TRAF-peptide interactions 11,13,18 . Most interestingly, the key aminoacids in USP7's MATHd interacting with all these different substrates are 164 DWGF 167 , which shape the peptide-binding pocket and, as indicated above, are distinctively conserved among UBPs.…”

Section: Ubiquitin Proteases (Ubps)contrasting

confidence: 39%

“…Most interestingly, the key aminoacids in USP7's MATHd interacting with all these different substrates are 164 DWGF 167 , which shape the peptide-binding pocket and, as indicated above, are distinctively conserved among UBPs. Other aminoacids participating in interaction account for the differences in affinity of the different substrates, but interactions with the DWGF, in particular with Trp165, are critical for the specificity of the binding 11,13,18 .…”

Section: Ubiquitin Proteases (Ubps)mentioning

confidence: 99%

“…Indeed, USP7 was originally identified by its interaction with ICP0 protein from herpes simplex virus 12 . USP7 also interacts with p53 and Mdm2 13 , and EpsteinBarr virus nuclear antigen 1 (EBNA1) protein 11 .…”

Section: Ubiquitin Proteases (Ubps)mentioning

confidence: 99%

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Phylogeny of the TRAF/MATH Domain

Zapata

Martínez-García²,

Lefebvre³

Advances in Experimental Medicine and Biology

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This chapter is dedicated to the memory of José Zapata Ruiz, my beloved father and strongest supporter. TLR AbstractThe TNF-Receptor Associated Factor (TRAF) domain (TD), also known as the meprin and TRAF-C homology (MATH) domain is a fold of seven anti-parallel β-helices that participates in protein-protein interactions. This fold is broadly represented among eukaryotes, where it is found associated with a discrete set of protein-domains. Virtually all protein families encompassing a TRAF/MATH domain seem to be involved in the regulation of protein processing and ubiquitination, strongly suggesting a parallel evolution of the TRAF/MATH domain and certain proteolysis pathways in eukaryotes.The restricted number of living organisms for which we have information of their genetic and protein make-up limits the scope and analysis of the MATH domain in evolution. However, the available information allows us to get a glimpse on the origins, distribution and evolution of the TRAF/MATH domain, which will be overviewed in this chapter.Introduction.

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Section: Ubiquitin Proteases (Ubps)contrasting

confidence: 39%

Section: Ubiquitin Proteases (Ubps)mentioning

confidence: 99%

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Phylogeny of the TRAF/MATH Domain

Zapata

Martínez-García²,

Lefebvre³

Advances in Experimental Medicine and Biology

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“…The deubiquitinating enzyme Herpes virusassociated ubiquitin-specific protease (HAUSP) has been shown to interact with and stabilize MDM2, MDM4 and p53. Structural studies indicate that both MDM2 and p53 can bind the same site on HAUSP, suggesting that they may compete with each other for this interaction (Sheng et al, 2006). In unstressed cells, the Death-domain associated protein (Daxx) would associate with both MDM2 and HAUSP, and the formation of this complex would reduce MDM2 auto-ubiquitination, enabling MDM2-p53 interactions, and thus p53 degradation.…”

Section: Biological Functionsmentioning

confidence: 99%

MDM2 and MDM4: p53 regulators as targets in anticancer therapy

Toledo

Wahl

2007

The International Journal of Biochemistry & Cell Biology

216

162

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The gene TP53, encoding transcription factor p53, is mutated or deleted in half of human cancers, demonstrating the crucial role of p53 in tumor suppression. Importantly, p53 inactivation in cancers can also result from the amplification / overexpression of its specific inhibitors MDM2 and MDM4 (also known as MDMX). The presence of wild-type p53 in those tumors with MDM2 or MDM4 overexpression stimulates the search for new therapeutic agents to selectively reactivate it. This short survey highlights recent insights into MDM2 and MDM4 regulatory functions and their implications for the design of future p53-based anticancer strategies. We now know that MDM2 and MDM4 inhibit p53 in distinct and complementary ways: MDM4 regulates p53 activity, while MDM2 mainly regulates p53 stability. Upon DNA damage, MDM2-dependent degradation of itself and MDM4 contribute significantly to p53 stabilization and activation. These and other data imply that the combined use of MDM2 and MDM4 antagonists in cancer cells expressing wild type p53 should activate p53 more significantly than agents that only antagonize MDM2, resulting in more effective anti-tumor activity.

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“…Recently, structural and biochemical studies of the p53-HAUSP and Mdm2-HAUSP interactions have elucidated more defined and precise binding domains within these proteins (Hu et al, 2006;Sheng et al, 2006). p53 and Mdm2 both bind within the N-terminal TRAF-like domain of HAUSP in a mutually exclusive manner.…”

mentioning

confidence: 99%

The p53–Mdm2–HAUSP complex is involved in p53 stabilization by HAUSP

et al. 2007

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The ubiquitin-specific protease HAUSP is a critical component of the p53-Mdm2 pathway by acting as a specific deubiquitinase for both p53 and Mdm2. Recent structural studies have indicated that p53 and Mdm2 bind to the N-terminal TRAF-like domain of HAUSP in a mutually exclusive manner. To understand the mechanism of HAUSP-mediated effects, we have created a p53 mutant that lacks HAUSP binding based on the crystal structure analysis. Indeed, this mutant p53 protein can be degraded by Mdm2 but fails to interact with HAUSP both in vitro and in vivo. Surprisingly, however, we have found that direct interaction between HAUSP and p53 is not absolutely required for it to antagonize efficiently Mdm2-mediated ubiquitination of p53 and that HAUSP is capable of enzymatically functioning in trans on p53 by using Mdm2 as a bridge. Further, we show that a trimeric protein complex containing p53, Mdm2 and HAUSP can exist in vivo, despite mutually exclusive binding, with Mdm2 serving as a binding mediator for p53 and HAUSP. These findings reveal the complication of HAUSP-mediated effects in the p53-Mdm2 interplay. It also has important implications for the development of novel chemotherapeutic compounds aimed at blocking this protein-protein interaction.

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Molecular recognition of p53 and MDM2 by USP7/HAUSP

Cited by 264 publications

References 17 publications

Phylogeny of the TRAF/MATH Domain

Phylogeny of the TRAF/MATH Domain

MDM2 and MDM4: p53 regulators as targets in anticancer therapy

The p53–Mdm2–HAUSP complex is involved in p53 stabilization by HAUSP

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