USP7 (Ubiquitin-Specific Peptidase 7, also HAUSP; encoded by the [USP7 gene](/genes/usp7)) is a major deubiquitinating enzyme (DUB) that removes ubiquitin from target proteins, rescuing them from proteasomal degradation. USP7 is a critical regulator of the p53/MDM2 axis, epigenetic maintenance, and neuronal proteostasis.
Overview
USP7 is a 128 kDa cysteine protease belonging to the ubiquitin-specific protease (USP) family of deubiquitinating enzymes<sup>[1]</sup>. It removes ubiquitin moieties from over 70 known substrates, with functional consequences ranging from protein stabilization to altered signaling. USP7's role in balancing the [ubiquitin-proteasome system](/mechanisms/ubiquitin-proteasome-system) makes it relevant to neurodegenerative protein aggregation disorders. [@faesen2011]
USP7 has a modular five-domain architecture<sup>[1]</sup>:
...
USP7 Protein (HAUSP Deubiquitinase)
Introduction
USP7 (Ubiquitin-Specific Peptidase 7, also HAUSP; encoded by the [USP7 gene](/genes/usp7)) is a major deubiquitinating enzyme (DUB) that removes ubiquitin from target proteins, rescuing them from proteasomal degradation. USP7 is a critical regulator of the p53/MDM2 axis, epigenetic maintenance, and neuronal proteostasis.
Overview
USP7 is a 128 kDa cysteine protease belonging to the ubiquitin-specific protease (USP) family of deubiquitinating enzymes<sup>[1]</sup>. It removes ubiquitin moieties from over 70 known substrates, with functional consequences ranging from protein stabilization to altered signaling. USP7's role in balancing the [ubiquitin-proteasome system](/mechanisms/ubiquitin-proteasome-system) makes it relevant to neurodegenerative protein aggregation disorders. [@faesen2011]
USP7 has a modular five-domain architecture<sup>[1]</sup>:
TRAF-like domain (N-terminal, aa 53-205): MATH domain that mediates interactions with p53, MDM2, and many substrates via a P/AxxS motif
Catalytic domain (aa 208-560): USP fold containing the Cys223-His464-Asp481 catalytic triad; cleaves isopeptide bonds between ubiquitin and substrates
Five UBL domains (C-terminal, aa 560-1084): Five tandem ubiquitin-like (UBL) folds that serve as scaffolds for allosteric activation and protein interactions
Catalytic Mechanism
USP7's catalytic domain adopts an auto-inhibited conformation in isolation<sup>[2]</sup>:
Apo state: The catalytic triad is misaligned; Cys223 is displaced from His464
[Hu M et al., Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde (2002) (2002)](https://doi.org/10.1016/S0092-8674(02)
[Faesen AC et al., Mechanism of USP7/HAUSP activation by its C-terminal ubiquitin-like domain and allosteric regulation by GMP-synthetase (2011) (2011)](https://doi.org/10.1016/j.molcel.2011.06.034)
[Kategaya L et al., USP7 small-molecule inhibitors interfere with ubiquitin binding (2017) (2017)](https://doi.org/10.1038/nature24006)
[Hao YH et al., USP7 acts as a molecular rheostat to promote WASH-dependent endosomal protein recycling and is mutated in a human neurodevelopmental disorder (2015) (2015)](https://doi.org/10.1016/j.molcel.2015.09.033)
[Bhatt DG et al., USP7 as a deubiquitinase for tau: implications for Alzheimer's disease (2020) (2020)](https://doi.org/10.1038/s41467-020-17120-x)
[Turnbull AP et al., Molecular basis of USP7 inhibition by selective small-molecule inhibitors (2017) (2017)](https://doi.org/10.1038/nature24451)