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Gene & Protein in Disease Structure and function of USP7

process of the substrate proteins . On the other hand, oncogene or as a tumor suppressor; therefore, it is essential
[3]
ubiquitination is a reversible and dynamic process, where to identify the specific substrate proteins, to understand
Ub molecule chains can be cleaved away from the target better the roles of USP7 in specific clinical setting. Thus,
proteins by certain deubiquitinating enzymes (DUBs), the structural domains of USP7 and their effects on the
protecting the target protein from degradation . In brief, USP7 activity, and the correlation between USP7 and
[4]
DUBs are a type of ubiquitin-specific proteases (USPs), intracellular signaling pathways, as well as the molecular
which can induce the hydrolysis of Ub chains from the mechanisms underlying the effects of USP7 on cancer and
specific substrate proteins, leading to recycling of the Ub other diseases are further discussed in this article. Finally,
molecules, processing of the Ub precursors, and reversing the application of USP7-specific inhibitors and their
of the Ub conjugation [5,6] . In terms of biological functions, potential applications in human diseases are included in
DUBs can regulate several cellular processes in humans, this article as well.
such as protein stabilization , gene transcription ,
[7]
[7]
signal transduction [8,9] , cell cycle progression, protein 2.1. The tumor necrosis factor-receptor associated
localization , DNA damage response, kinase factor (TRAF) domain
[10]
activation [11,12] , and many other functions. USP7 belongs to the UBP subfamily featured with an
[25]
Further, there are around 100 DUBs in human cells, N-terminal TRAF-like domain . The TRAF domain
which are able to reverse the ubiquitination reaction consists of 160–165 amino acid residues, which can
[26]
by removing the covalently attached Ub molecules mediate substrate recognition and interaction . It is well-
from the substrates. Based on their structure and known that TRAF domain binds to both p53 and HDM2,
functional characteristics, DUBs can be divided into thereby mediating their deubiquitination [26,27] . However,
five subfamilies: (1) USPs, the largest subfamily; (2) the deletion of the N-terminal TRAF-like domain does
Ub C-terminal hydrolase; (3) ovarian tumor; (4) not prevent the deubiquitination of p53 and HDM2 by
Machado-Josephin disease protein; and (5) Jab1/ USP7, suggesting the presence of a secondary binding site
Mov34/Mpr1-Pad1N-terminal+(JAMM) [13] . USP7 is a in USP7 with the substrate proteins. Later, this secondary
cysteine protease, which belongs to the USP subfamily. binding motif in USP7 is believed to be the ubiquitin-
It has been widely reported that USP7 interacts with the like (UBL) domain , indicating that there are different
[27]
substrates to prevent ubiquitination and degradation binding modes between USP7 and the substrates.
of the target proteins [14] . In this review, the recent
research advances about USP7 in terms of its structure, 2.2. The UBL domain
pathological processes, and development as specific In addition to the TRAF domain, UBL domain is another
inhibitors are discussed. common structural domain to UBPs. Most of the proteins
within the UBP subfamily have one or more UBL domains,
2. The structure of the USP7 including USP4, USP6, USP7, USP9X/Y, USP11, USP14,
USP7, also known as herpes virus-associated ubiquitin- USP15, USP19, USP24, USP31, USP32, USP34, USP43,
[28]
specific protease (HAUSP), has been demonstrated to USP47, USP48, and USP52 . Of note, the UBL domain
participate in various pathological processes and diseases, exhibits different regulatory functions. For example, the
including neurological disorders, metabolic disorders, UBL domain in USP4 has dual functions; it modulates
immune dysfunction, and particularly carcinogenesis. USP4 localization to the proteasome to enhance its
In addition, USP7 is highly expressed in different types catalytic activity, and at the same time, the UBL domain
of cancers, including breast cancer , medulloblastoma can mimic Ub molecule and competes for Ub binding,
[15]
cancer , T-cell leukemia , ovarian cancer , lung subsequently causing a reduction in the ubiquitination
[16]
[17]
[18]
[29]
[20]
[19]
cancer , and multiple myeloma (MM) . Furthermore, of the substrate . Interestingly, USP7 has five UBL
USP7 is closely related to malignant progression through domains (UBL1/2/3/4/5) at the C-terminus spanning
its deubiquitinating activity in stabilizing the oncogene from 560 to 1050 amino acids, and they are organized in
[20]
proteins, such as c-Maf and MafB transcription factors , a UBL1/2-UBL3-UBL4/5 sequence. The last two of the
E3 Ub ligase human homolog of double minute 2 (HDM2) UBL domains are found to modulate the catalytic activity
protein , oncoprotein c-Myc, and enhancer of zeste of USP7, specifically, by promoting a conformational
[21]
homolog 2 (EZH2) protein [22,23] . Interestingly, USP7 also change of USP7 through interacting with the catalytic
has been shown to stabilize several tumor suppressor domain (CD), leading to binding and reshaping of the
proteins, including p53 and phosphatase and tensin catalytic center [25,29,30] . In contrast, in the absence of these
homolog (PTEN) [10,24] . Due to the diversity of its substrates, UBL domains, USP7 loses its catalytic activity about
it is difficult to determine whether USP7 functions as an 100-fold , meanwhile the UBL4/5 domains can activate
[31]
Volume 1 Issue 2 (2022) 2 https://doi.org/10.36922/gpd.v1i2.118