Deubiquitinating enzyme

Last updated
USP21 (blue) covalently linked to linear diubiquitin aldehyde (green). The C-terminus of the ubiquitin protrudes through the active site of USP21 (lower right). Ubiquitin and USP21.png
USP21 (blue) covalently linked to linear diubiquitin aldehyde (green). The C-terminus of the ubiquitin protrudes through the active site of USP21 (lower right).
Ubiquitin-AMC,a fluorogenic substrate for a wide range of DUBs Ub AMC.jpeg
Ubiquitin-AMC,a fluorogenic substrate for a wide range of DUBs

Deubiquitinating enzymes (DUBs), also known as deubiquitinating peptidases, deubiquitinating isopeptidases, deubiquitinases, ubiquitin proteases, ubiquitin hydrolases, or ubiquitin isopeptidases, are a large group of proteases [1] that cleave ubiquitin from proteins. [2] Ubiquitin is attached to proteins in order to regulate the degradation of proteins via the proteasome and lysosome; coordinate the cellular localisation of proteins; activate and inactivate proteins; and modulate protein-protein interactions. [3] [4] [5] DUBs can reverse these effects by cleaving the peptide or isopeptide bond between ubiquitin and its substrate protein. In humans there are nearly 100 DUB genes, which can be classified into two main classes: cysteine proteases and metalloproteases. The cysteine proteases comprise ubiquitin-specific proteases (USPs), ubiquitin C-terminal hydrolases (UCHs), Machado-Josephin domain proteases (MJDs) and ovarian tumour proteases (OTU). The metalloprotease group contains only the Jab1/Mov34/Mpr1 Pad1 N-terminal+ (MPN+) (JAMM) domain proteases. [2]

Contents

Classes

In humans there are 102 putative DUB genes, which can be classified into two main classes: cysteine proteases and metalloproteases, consisting of 58 ubiquitin-specific proteases (USPs), 4 ubiquitin C-terminal hydrolases (UCHs), 5 Machado-Josephin domain proteases (MJDs), 14 ovarian tumour proteases (OTU), and 14 Jab1/Mov34/Mpr1 Pad1 N-terminal+ (MPN+) (JAMM) domain-containing genes. 11 of these proteins are predicted to be non-functional, leaving 79 functional enzymes. [6] In yeast, the USPs are known as ubiquitin-specific-processing proteases (UBPs).

Cysteine proteases

There are six main superfamilies of cysteine protease DUBs: [7]

UCH
PDB 2hd5 EBI.jpg
USP2 in complex with ubiquitin.
Identifiers
SymbolUCH
Pfam PF00443
Pfam clan CL0125
InterPro IPR001394
PROSITE PDOC00750
MEROPS C19
SCOP2 1nb8 / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

There is also a little known putative group of DUBs called the permutated papain fold peptidases of dsDNA viruses and eukaryote (PPPDEs) superfamily, which, if shown to be bona fide DUBs, would be the seventh in the cysteine protease class. [11]

Metalloproteases

The Jab1/Mov34/Mpr1 Pad1 N-terminal+ (MPN+) (JAMM) domain superfamily proteins bind zinc and hence are metalloproteases. [7]

Role of deubiquitinating enzymes

Schematic representation DUBs function DUBs.png
Schematic representation DUBs function

DUBs play several roles in the ubiquitin pathway. One of the best characterised functions of DUBs is the removal of monoubiqutin and polyubiquitin chains from proteins. These modifications are a post translational modification (addition to a protein after it has been made) where single ubiquitin proteins or chains of ubiquitin are added to lysines of a substrate protein. These ubiquitin modifications are added to proteins by the ubiquitination machinery; ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s). The end result is ubiquitin bound to lysine residues via an isopeptide bond. [12] Proteins are affected by these modifications in a number of ways: they regulate the degradation of proteins via the proteasome and lysosome; coordinate the cellular localisation of proteins; activate and inactivate proteins; and modulate protein-protein interactions. [3] [4] [5] DUBs play the antagonistic role in this axis by removing these modifications, therefore reversing the fate of the proteins. [2] In addition, a less understood role of DUBs is the cleavage of ubiquitin-like proteins such as SUMO and NEDD8. Some DUBs may have the ability to cleave isopeptide bonds between these proteins and substrate proteins. [13]

They activate ubiquitin by the proteolysis (breaking down) of the inactive expressed forms of ubiquitin. Ubiquitin is encoded in mammals by 4 different genes: UBA52, RPS27A, UBB and UBC. A similar set of genes is found in other eukaryotes such as yeast. The UBA52 and RPS27A genes produce ubiquitin that is fused to ribosomal proteins and the UBB and UBC genes produce polyubiquitin (a chain of ubiquitin joined by their C- and N-termini). [14] [15] DUBs cleave the ubiquitin from these proteins, producing active single units of ubiquitin. [2]

DUBs also cleave single ubiquitin proteins that may have had their C-terminal tails accidentally bound to small cellular nucleophiles. [2] These ubiquitin-amides and ubiquitin-thioesters may be formed during standard ubiquitination reactions by the E1-E2-E3 cascade. Glutathione and polyamines are two nucleophiles that might attack the thiolester bond between ubiquitin and these enzymes. Ubiquitin C-terminal hydrolase is an example of the DUB that hydrolyses these bonds with broad specificity. [13] [16]

Free polyubiquitin chains are cleaved by DUBs to produce monoubiquitin. The chains may be produced by the E1-E2-E3 machinery in the cell free from any substrate protein. Another source of free polyubiquitin is the product of ubiquitin-substrate cleavage. If DUBs cleave the base of the polyubiquitin chain that is attached to a protein, the whole chain will become free and needs to be recycled by DUBs. [2]

Domains

Catalytic domain of USP7. Catalytic domains of USPs can be visualised as the fingers palm and thumb of a hand. Ubiquitin fits into the hand with its C-terminus poking through between the thumb and palm. Catalytic domain of USP7.png
Catalytic domain of USP7. Catalytic domains of USPs can be visualised as the fingers palm and thumb of a hand. Ubiquitin fits into the hand with its C-terminus poking through between the thumb and palm.

DUBs often contain a catalytic domain surrounded by one or more accessory domains, some of which contribute to target recognition. These additional domains include domain present in ubiquitin-specific proteases (DUSP) domain; ubiquitin-like (UBL) domain; meprin and TRAF homology (MATH) domain; zinc-finger ubiquitin-specific protease (ZnF-UBP) domain; zinc-finger myeloid, nervy and DEAF1 (ZnF-MYND) domain; ubiquitin-associated (UBA) domain; CHORD-SGT1 (CS) domain; microtubule-interacting and trafficking (MIT) domain; rhodenase-like domain; TBC/RABGAP domain; and B-box domain. [6] [17]

Catalytic domain

The catalytic domain of DUBs is what classifies them into particular groups; USPs, OTUs, MJDs, UCHs and MPN+/JAMMs. The first 4 groups are cysteine proteases, whereas the latter is a zinc metalloprotease. The cysteine protease DUBs are papain-like and thus have a similar mechanism of action. They use either catalytic dyads or triads (either two or three amino acids) to catalyse the hydrolysis of the amide bonds between ubiquitin and the substrate. The active site residues that contribute to the catalytic activity of the cysteine protease DUBs are cysteine (dyad/triad), histidine (dyad/triad) and aspartate or asparagine (triad only). The histidine is polarised by the aspartate or asparagine in catalytic triads or by other ways in dyads. This polarised residue lowers the pKa of the cysteine, allowing it to perform a nucleophilic attack on the isopeptide bond between the ubiquitin C-terminus and the substrate lysine. Metalloproteases coordinate zinc ions with histidine, aspartate and serine residues, which activate water molecules and allows them to attack the isopeptide bond. [18] [19]

UBL

Ubiquitin-like (UBL) domains have a similar structure (fold) to ubiquitin, except they lack the terminal glycine residues. 18 USPs are proposed to have UBL domains. Only 2 other DUBs have UBLs outside the USP group: OTU1 and VCPIP1. USP4, USP7, USP11, USP15, USP32, USP40 and USP47 have multiple UBL domains. Sometimes the UBL domains are in tandem, such as in USP7 where 5 tandem C-terminal UBL domains are present. USP4, USP6, USP11, USP15, USP19, USP31, USP32 and USP43 have UBL domains inserted into the catalytic domain. The functions of UBL domains are different between USPs, but commonly they regulate USP catalytic activity. They can coordinate localisation at the proteasome (USP14); negatively regulate USPs by competing for the catalytic site of the USP (USP4), and induce conformational changes to increase catalytic activity (USP7). [17] [20] [21] Like other UBL domains, the structure of USP UBL domains show a β-grasp fold. [22] [23]

DUSP

DUSP domain
PDB 1w6v EBI.jpg
Solution structure of the DUSP domain of HUSP15.
Identifiers
SymbolDUSP
Pfam PF06337
InterPro IPR006615
MEROPS C19
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Single or multiple tandem DUSP domains of approximately 120 residues are found in six USPs. The function of the DUSP domain is currently unknown but it may play a role in protein-protein interaction, in particular to DUBs substrate recognition. This is predicted because of the hydrophobic cleft present in the DUSP domain of USP15 and that some protein interactions with DUSP containing USPs do not occur without these domains. The DUSP domain displays a novel tripod-like fold comprising three helices and an anti-parallel beta-sheet made of three strands. This fold resembles the legs (helices) and seat (beta-sheet) of the tripod. Within most DUSP domains in USPs there is a conserved sequence of amino acids known as the PGPI motif. This is a sequence of four amino acids; proline, glycine, proline and isoleucine, which packs against the three-helix bundle and is highly ordered. [6] [24]

Role in disease

The full extent of the role of DUBs in diseases remains to be elucidated. Their involvement in disease is predicted due to known roles in physiological processes that are involved in disease states; including cancer and neurological disorders. [25]

The enzyme USP28 is over-expressed in different types of cancer such as colon or lung. In addition, USP28 deubiquitinates and stabilizes important oncogenes such as c-Myc, Notch1, c-jun or ΔNp63. [26] [27] [28] In squamous tumors, USP28 regulates the resistance to chemotherapy regulating DNA repair via ΔNp63-Fanconia anemia pathway axis. [29]

The deubiquitinating enzymes UCH-L3 and YUH1 are able to hydrolyse mutant ubiquitin UBB+1 despite the fact that the glycine at position 76 is mutated. [30]

UCH-L1 levels are high in various types of malignancies (cancer). [31]

Role in the cell cycle

DUBs play an active role in modulating the cell cycle. Ubiquitin-specific-processing protease (USP) is a family of deubiquitinating enzymes that play a crucial role in cell cycle regulation. [32] Two such enzymes include USP17 and USP44. USP17 regulates pathways responsible for progressing cells through the cell cycle. [33] Its targets include regulators of Ras, CDK2, and Cyclin A. [34] USP44 plays an important role in anaphase initiation. [35] New research into the mitotic checkpoint has revealed a novel role for USP44 in regulating cell cycle progression. [35]

USP regulation of Ras

The ERK Pathway allows for the transduction of external mitogenic signals into intracellular signals promoting cellular proliferation. One of the key regulators of this pathways is Ras, a GTPase that, upon activation, binds GTP to “turn on” the subsequent signaling cascade. Ras converting enzyme 1 (RCE1) post-translationally cleaves the 3 residues on the C-terminus of Ras, allowing Ras to properly localize to the plasma membrane. [36]

USP17 acts to deubiquitinate K63-ubiquitin domains on RCE1. [34] Such stabilization of RCE1 allows for proper localization of Ras, thus promoting proliferation upon activation of early receptors in the ERK Pathway. Ras hyperactivity can result in cell cycle dysregulation. [37] Thus, regulation of Ras through USP17 acts as another point in Ras regulation.

USP regulation of G1-S transition

Cyclin-dependent kinases (CDKs) are a family of enzymes that phosphorylate serine and threonine residues to drive the cell through the cell cycle. Activation of CDK2 is critical for the G1-S transition. For CDK2 to be activated, cyclin A must bind to the cyclin-dependent kinase complex (CDKC). Cell division cycle 25A (CDC25A) is a phosphatase that removes an inhibitory phosphate group from CDK2. [38] While ubiquitination would mark CDC25A for degradation, thus blocking progression to S phase, USP17 deubiquitinates CDC25A. [34] An increase in CDC25A stability promotes CDKC activity, thus driving the cell through the G1-S transition.

USP17 also regulates cell cycle progression by acting on SETD8 to downregulate transcription of cyclin-dependent kinase inhibitor 1 (CDKN1A), also known as p21. [34] CDKN1A binds to and inhibits CDK2 using its N-terminal binding domain, thus blocking progression through the G1-S transition. SETD8, a methyltransferase, uses S-Adenosyl methionine to methylate the Lys20 residue of histone 4, resulting in the condensation of chromosomes. [39] This compaction of the DNA downregulates CDKN1A transcription. USP17 deubiquitinates SETD8, thus reducing its propensity for degradation and increasing its intracellular stability. [34] The resulting downregulation in CDKN1A transcription promotes CDK2 activity, allowing the cell to progress through the G1-S transition. See schematic of the role of DUBs in the cell cycle regulation. [34]

Schematic of the role of DUBs in the cell cycle regulation DUBs in the cell cycle.png
Schematic of the role of DUBs in the cell cycle regulation

USP44 in anaphase initiation

The spindle checkpoint (also referred to as the mitotic checkpoint) ensures proper separation of chromosomes. Broadly, the mitotic checkpoint promotes fidelity in chromosomal segregation, increasing the likelihood that each daughter cell receives only one duplicated chromosome. [40] Such a mechanism is crucial, as errors in chromosomal separation have been implicated in cancer, birth defects, and antibiotic resistance in pathogens. [41] One of the core regulator proteins is the anaphase-promoting complex (APC/C). APC/C ubiquitinates securin. [42] The resulting destruction of securing release separase, [40] which hydrolyzes cohesion – the protein that binds sister chromatids together.

New research from Stegmeier and colleagues [35] published in the journal Nature demonstrates a crucial role for USP44 in regulating the spindle checkpoint. Using an shRNA screen, USP44 was identified to stabilize the inhibition of APC/C [35] The binding of CDC20 to APC/C is required for the ubiquitination of securin. [43] A protein called hMAD2 can form an inactive trimer with APC and CDC20, forming the hMAD2-CDC-APC complex. [43] Upon the ubiquitination of CDC20 by UbcH10, hMAD2 dissociates, and APC/C becomes active. [44] It is important to note that ubiquitination of CDC20 does not serve to mark it for degradation, but rather promote dissociation of hMAD2 from the hMAD2-CDC-APC complex. USP44, a ubiquitin-specific-processing protease, can stabilize the inactive hMAD2-CDC-APC complex by counteracting UbcH10 ubiquitination. This blocks hMAD2 dissociation and allows for proper regulation of APC/C, keeping it inactive until proper attachment of the mitotic spindle. Upon proper attachment, switch-like behavior allows for the activation of APC/C. [35] This results in the cleavage of cohesion, allowing for the separation of sister chromatids.

Role in p53-mediated DNA damage repair

DNA damage can prove catastrophic for an organism. Mechanisms for DNA mutation include oxidative stress, DNA replication errors, exogenous carcinogens, radiation, and spontaneous base mutation. Upon DNA damage, cell cycle progression is halted to prevent propagation of the mutation. The TP53 gene (also known as p53) is crucial in ensuring the conservation of the genome. [45] Deubiquitinating enzymes play an integral role in maintaining p53’s function.

In healthy cells, p53 activates the E3 ubiquitin ligase MDM2 which in turn ubiquitinates p53. This creates a negative feedback loop, whereby the degradation of p53 allows for cells to flow through the cell cycle. [46] [ circular reference ] Upon DNA damage, Ubiquitin-specific-processing protease 7 (USP7) stabilizes p53 by cleaving ubiquitin. [47] For USP7 to deubiquitinate p53, it must localize to the nucleus. However, no nuclear localization sequence (NLS) has been found. [48] Despite no known NLS, one study showed that, upon deletion of USP7’s N-terminus, no nuclear localization occurred. [48] It is possible that other proteins facilitate nuclear entry of USP7.

Once stabilized, p53 can exert its tumor suppression function. Downstream pathways of p53 act to either halt cell cycle progression in G1 or G2 phases of the cell cycle [49] or promote cell-death, depending on the severity of the DNA damage. [50] See schematic of the role of USP7 in the p53-dependent pathway. [49] or promote cell-death, depending on the severity of the DNA damage. [50] See schematic of the role of USP7 in the p53-dependent pathway. [50]

Schematic of the role of USP7 in the p53-dependent pathway. Role of USP7 in p53-dependent path.png
Schematic of the role of USP7 in the p53-dependent pathway.

Related Research Articles

<span class="mw-page-title-main">Proteasome</span> Protein complexes which degrade unnecessary or damaged proteins by proteolysis

Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.

<span class="mw-page-title-main">Ubiquitin</span> Regulatory protein found in most eukaryotic tissues

Ubiquitin is a small regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ubiquitously. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A.

<span class="mw-page-title-main">Ubiquitin ligase</span> Protein

A ubiquitin ligase is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the protein substrate. In simple and more general terms, the ligase enables movement of ubiquitin from a ubiquitin carrier to another thing by some mechanism. The ubiquitin, once it reaches its destination, ends up being attached by an isopeptide bond to a lysine residue, which is part of the target protein. E3 ligases interact with both the target protein and the E2 enzyme, and so impart substrate specificity to the E2. Commonly, E3s polyubiquitinate their substrate with Lys48-linked chains of ubiquitin, targeting the substrate for destruction by the proteasome. However, many other types of linkages are possible and alter a protein's activity, interactions, or localization. Ubiquitination by E3 ligases regulates diverse areas such as cell trafficking, DNA repair, and signaling and is of profound importance in cell biology. E3 ligases are also key players in cell cycle control, mediating the degradation of cyclins, as well as cyclin dependent kinase inhibitor proteins. The human genome encodes over 600 putative E3 ligases, allowing for tremendous diversity in substrates.

<span class="mw-page-title-main">UBA1</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-like modifier activating enzyme 1 (UBA1) is an enzyme which in humans is encoded by the UBA1 gene. UBA1 participates in ubiquitination and the NEDD8 pathway for protein folding and degradation, among many other biological processes. This protein has been linked to X-linked spinal muscular atrophy type 2, neurodegenerative diseases, and cancers.

<span class="mw-page-title-main">Endoplasmic-reticulum-associated protein degradation</span>

Endoplasmic-reticulum-associated protein degradation (ERAD) designates a cellular pathway which targets misfolded proteins of the endoplasmic reticulum for ubiquitination and subsequent degradation by a protein-degrading complex, called the proteasome.

<span class="mw-page-title-main">USP7</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-specific-processing protease 7 (USP7), also known as ubiquitin carboxyl-terminal hydrolase 7 or herpesvirus-associated ubiquitin-specific protease (HAUSP), is an enzyme that in humans is encoded by the USP7 gene.

<span class="mw-page-title-main">Ubiquitin D</span> Protein-coding gene in the species Homo sapiens

Ubiquitin D is a protein that in humans is encoded by the UBD gene, also known as FAT10. UBD acts like ubiquitin, by covalently modifying proteins and tagging them for destruction in the proteasome.

<span class="mw-page-title-main">USP8</span> Protein-coding gene in the species Homo sapiens

Ubiquitin carboxyl-terminal hydrolase 8 is an enzyme that in humans is encoded by the USP8 gene.

<span class="mw-page-title-main">USP6</span> Protein-coding gene in the species Homo sapiens

Ubiquitin carboxyl-terminal hydrolase 6 (USB6), also termed TRE17 and Tre-2, is a deubiquitinating enzyme that in humans is encoded by the hominid USP6 gene located at band 13.2 on the short arm of chromosome 17. Deubiquitinating enzymes (DUBs) are enzymes that act within cells to remove ubiquitins from various functionally important proteins. Ubiquitin enzymes add ubiquitin to these proteins and thereby regulate their cellular location, alter their activity, and/or promote their degradation. By deubiquitinating these proteins, DUBs counter the effects of the ubiquinating enzymes and contribute to regulating the actions of the targeted proteins. In normal adult tissues, USP6 is highly expressed in testicle tissue, modestly expressed in ovarian tissue, and absent or minimally expressed in other tissues. It is also highly expressed in fetal brain tissue. The specific functions of USP6 are poorly defined primarily because its presence is restricted to primates: there are no available animal models to determine the effects of its deletion, although some studies suggest that UPSP6 contributes to normal brain development. In all events, USP6 has gained wide interest because of its abnormally increased expression by the neoplastic cells in various tumors derived from mesenchymal tissue.

<span class="mw-page-title-main">USP10</span> Protein-coding gene in the species Homo sapiens

Ubiquitin specific peptidase 10, also known as USP10, is an enzyme which in humans is encoded by the USP10 gene.

<span class="mw-page-title-main">USP4</span> Protein-coding gene in the species Homo sapiens

Ubiquitin specific protease 4 (USP4) is an enzyme that cleaves ubiquitin from a number of protein substrates. Prior to the standardization of nomenclature USP4 was known as UNP, and was one of the first deubiquitinating enzymes to be identified in mammals. In the mouse and human the USP4 protein is encoded by a gene containing 22 exons.

<span class="mw-page-title-main">USP11</span> Protein-coding gene in the species Homo sapiens

Ubiquitin carboxyl-terminal hydrolase or Ubiquitin specific protease 11 is an enzyme that in humans is encoded by the USP11 gene. USP11 belongs to the Ubiquitin specific proteases family (USPs) which is a sub-family of the Deubiquitinating enzymes (DUBs).USPs are multiple domain proteases and belong to the C19 cysteine proteases sub‒family. Depending on their domain architecture and position there is different homology between the various members. Generally the largest domain is the catalytic domain which harbours the three residue catalytic triad that is included inside conserved motifs. The catalytic domain also contains sequences that are not related with the catalysis function and their role is mostly not clearly understood at present, the length of these sequences varies for each USP and therefore the length of the whole catalytic domain can range from approximately 295 to 850 amino acids. Particular sequences inside the catalytic domain or at the N‒terminus of some USPs have been characterised as UBL and DUSP domains respectively. In some cases, regarding the UBL domains, it has been reported to have a catalysis enhancing function as in the case of USP7. In addition, a so‒called DU domain module is the combination of a DUSP domain followed by a UBL domain separated by a linker and is found in USP11 as well as in USP15 and USP4.

<span class="mw-page-title-main">USP1</span> Protein-coding gene in the species Homo sapiens

Ubiquitin carboxyl-terminal hydrolase 1 is an enzyme that in humans is encoded by the USP1 gene.

<span class="mw-page-title-main">USP15</span> Protein-coding gene in the species Homo sapiens

Ubiquitin carboxyl-terminal hydrolase 15 is an enzyme that in humans is encoded by the USP15 gene.

<span class="mw-page-title-main">USP2</span> Protein-coding gene in the species Homo sapiens

Ubiquitin carboxyl-terminal hydrolase 2 is an enzyme that in humans is encoded by the USP2 gene.

<span class="mw-page-title-main">ATG7</span> Protein-coding gene in the species Homo sapiens

Autophagy related 7 is a protein in humans encoded by ATG7 gene. Related to GSA7; APG7L; APG7-LIKE.

<span class="mw-page-title-main">USP20</span> Protein-coding gene in the species Homo sapiens

Ubiquitin carboxyl-terminal hydrolase 20 is an enzyme that in humans is encoded by the USP20 gene.

<span class="mw-page-title-main">Ubiquitin-like protein</span> Family of small proteins

Ubiquitin-like proteins (UBLs) are a family of small proteins involved in post-translational modification of other proteins in a cell, usually with a regulatory function. The UBL protein family derives its name from the first member of the class to be discovered, ubiquitin (Ub), best known for its role in regulating protein degradation through covalent modification of other proteins. Following the discovery of ubiquitin, many additional evolutionarily related members of the group were described, involving parallel regulatory processes and similar chemistry. UBLs are involved in a widely varying array of cellular functions including autophagy, protein trafficking, inflammation and immune responses, transcription, DNA repair, RNA splicing, and cellular differentiation.

<span class="mw-page-title-main">USP27X</span> Enzyme

The ubiquitin carboxyl-terminal hydrolase 27, also known as deubiquitinating enzyme 27, ubiquitin thioesterase 27 and USP27X, is a deubiquitinating enzyme which is mainly characterized for cleaving ubiquitin (Ub) from proteins and other molecules. Ubiquitin binds to proteins so as to regulate the degradation of them via the proteasome and lysosome among many other functions.

<span class="mw-page-title-main">Nidoviral papain-like protease</span> Papain-like protease protein domain

The nidoviral papain-like protease is a papain-like protease protein domain encoded in the genomes of nidoviruses. It is expressed as part of a large polyprotein from the ORF1a gene and has cysteine protease enzymatic activity responsible for proteolytic cleavage of some of the N-terminal viral nonstructural proteins within the polyprotein. A second protease also encoded by ORF1a, called the 3C-like protease or main protease, is responsible for the majority of further cleavages. Coronaviruses have one or two papain-like protease domains; in SARS-CoV and SARS-CoV-2, one PLPro domain is located in coronavirus nonstructural protein 3 (nsp3). Arteriviruses have two to three PLP domains. In addition to their protease activity, PLP domains function as deubiquitinating enzymes (DUBs) that can cleave the isopeptide bond found in ubiquitin chains. They are also "deISGylating" enzymes that remove the ubiquitin-like domain interferon-stimulated gene 15 (ISG15) from cellular proteins. These activities are likely responsible for antagonizing the activity of the host innate immune system. Because they are essential for viral replication, papain-like protease domains are considered drug targets for the development of antiviral drugs against human pathogens such as MERS-CoV, SARS-CoV, and SARS-CoV-2.

References

  1. ↑ Wilkinson KD (December 1997). "Regulation of ubiquitin-dependent processes by deubiquitinating enzymes". FASEB Journal. 11 (14): 1245–56. doi:10.1096/fasebj.11.14.9409543. PMID   9409543. S2CID   11788220.
  2. 1 2 3 4 5 6 Reyes-Turcu FE, Ventii KH, Wilkinson KD (2009). "Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes". Annual Review of Biochemistry. 78: 363–97. doi:10.1146/annurev.biochem.78.082307.091526. PMC   2734102 . PMID   19489724.
  3. 1 2 Glickman MH, Ciechanover A (April 2002). "The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction". Physiological Reviews. 82 (2): 373–428. doi:10.1152/physrev.00027.2001. PMID   11917093.
  4. 1 2 Mukhopadhyay D, Riezman H (January 2007). "Proteasome-independent functions of ubiquitin in endocytosis and signaling". Science. 315 (5809): 201–5. Bibcode:2007Sci...315..201M. doi:10.1126/science.1127085. PMID   17218518. S2CID   35434448.
  5. 1 2 Schnell JD, Hicke L (September 2003). "Non-traditional functions of ubiquitin and ubiquitin-binding proteins". The Journal of Biological Chemistry. 278 (38): 35857–60. doi: 10.1074/jbc.R300018200 . PMID   12860974.
  6. 1 2 3 Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK, Bernards R (December 2005). "A genomic and functional inventory of deubiquitinating enzymes". Cell. 123 (5): 773–86. doi:10.1016/j.cell.2005.11.007. hdl: 1874/20959 . PMID   16325574. S2CID   15575576.
  7. 1 2 Amerik AY, Hochstrasser M (November 2004). "Mechanism and function of deubiquitinating enzymes". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1695 (1–3): 189–207. doi: 10.1016/j.bbamcr.2004.10.003 . PMID   15571815.
  8. ↑ Abdul Rehman SA, Kristariyanto YA, Choi SY, Nkosi PJ, Weidlich S, Labib K, et al. (July 2016). "MINDY-1 Is a Member of an Evolutionarily Conserved and Structurally Distinct New Family of Deubiquitinating Enzymes". Molecular Cell. 63 (1): 146–55. doi:10.1016/j.molcel.2016.05.009. PMC   4942677 . PMID   27292798.
  9. ↑ Kwasna D, Abdul Rehman SA, Natarajan J, Matthews S, Madden R, De Cesare V, et al. (April 2018). "Discovery and Characterization of ZUFSP/ZUP1, a Distinct Deubiquitinase Class Important for Genome Stability". Molecular Cell. 70 (1): 150–164.e6. doi:10.1016/j.molcel.2018.02.023. PMC   5896202 . PMID   29576527.
  10. ↑ Hermanns, Thomas; Pichlo, Christian; Woiwode, Ilka; Klopffleisch, Karsten; Witting, Katharina F.; Ovaa, Huib; Baumann, Ulrich; Hofmann, Kay (2018-02-23). "A family of unconventional deubiquitinases with modular chain specificity determinants". Nature Communications. 9 (1): 799. doi:10.1038/s41467-018-03148-5. ISSN   2041-1723. PMC   5824887 . PMID   29476094.
  11. ↑ Iyer LM, Koonin EV, Aravind L (November 2004). "Novel predicted peptidases with a potential role in the ubiquitin signaling pathway". Cell Cycle. 3 (11): 1440–50. doi:10.4161/cc.3.11.1206. PMID   15483401.
  12. ↑ Kerscher O, Felberbaum R, Hochstrasser M (2006). "Modification of proteins by ubiquitin and ubiquitin-like proteins". Annual Review of Cell and Developmental Biology. 22: 159–80. doi:10.1146/annurev.cellbio.22.010605.093503. PMID   16753028. S2CID   17584645.
  13. 1 2 Wing SS (May 2003). "Deubiquitinating enzymes--the importance of driving in reverse along the ubiquitin-proteasome pathway". The International Journal of Biochemistry & Cell Biology. 35 (5): 590–605. doi:10.1016/s1357-2725(02)00392-8. PMID   12672452.
  14. ↑ Kimura Y, Tanaka K (June 2010). "Regulatory mechanisms involved in the control of ubiquitin homeostasis". Journal of Biochemistry. 147 (6): 793–8. doi: 10.1093/jb/mvq044 . PMID   20418328.
  15. ↑ Ozkaynak E, Finley D, Solomon MJ, Varshavsky A (May 1987). "The yeast ubiquitin genes: a family of natural gene fusions". The EMBO Journal. 6 (5): 1429–39. doi:10.1002/j.1460-2075.1987.tb02384.x. PMC   553949 . PMID   3038523.
  16. ↑ Pickart CM, Rose IA (July 1985). "Ubiquitin carboxyl-terminal hydrolase acts on ubiquitin carboxyl-terminal amides". The Journal of Biological Chemistry. 260 (13): 7903–10. doi: 10.1016/S0021-9258(17)39538-8 . PMID   2989266.
  17. 1 2 Komander D, Clague MJ, Urbé S (August 2009). "Breaking the chains: structure and function of the deubiquitinases". Nature Reviews. Molecular Cell Biology. 10 (8): 550–63. doi:10.1038/nrm2731. PMID   19626045. S2CID   19149247.
  18. ↑ Komander D (2010). "Mechanism, Specificity and Structure of the Deubiquitinases". Conjugation and Deconjugation of Ubiquitin Family Modifiers. Subcellular Biochemistry. Vol. 54. pp. 69–87. doi:10.1007/978-1-4419-6676-6_6. ISBN   978-1-4419-6675-9. PMID   21222274.{{cite book}}: |journal= ignored (help)
  19. ↑ Chapman HA, Riese RJ, Shi GP (1997). "Emerging roles for cysteine proteases in human biology". Annual Review of Physiology. 59: 63–88. doi:10.1146/annurev.physiol.59.1.63. PMID   9074757.
  20. ↑ Faesen AC, Luna-Vargas MP, Sixma TK (June 2012). "The role of UBL domains in ubiquitin-specific proteases". Biochemical Society Transactions. 40 (3): 539–45. doi:10.1042/BST20120004. PMID   22616864.
  21. ↑ Ye Y, Scheel H, Hofmann K, Komander D (December 2009). "Dissection of USP catalytic domains reveals five common insertion points". Molecular BioSystems. 5 (12): 1797–808. doi:10.1039/b907669g. PMID   19734957.
  22. ↑ Elliott PR, Liu H, Pastok MW, Grossmann GJ, Rigden DJ, Clague MJ, et al. (November 2011). "Structural variability of the ubiquitin specific protease DUSP-UBL double domains". FEBS Letters. 585 (21): 3385–90. doi:10.1016/j.febslet.2011.09.040. PMID   22001210. S2CID   5312371.
  23. ↑ Harper S, Besong TM, Emsley J, Scott DJ, Dreveny I (September 2011). "Structure of the USP15 N-terminal domains: a β-hairpin mediates close association between the DUSP and UBL domains". Biochemistry. 50 (37): 7995–8004. doi:10.1021/bi200726e. PMID   21848306.
  24. ↑ de Jong RN, Ab E, Diercks T, Truffault V, Daniëls M, Kaptein R, Folkers GE (February 2006). "Solution structure of the human ubiquitin-specific protease 15 DUSP domain". The Journal of Biological Chemistry. 281 (8): 5026–31. doi: 10.1074/jbc.M510993200 . PMID   16298993.
  25. ↑ Singhal S, Taylor MC, Baker RT (October 2008). "Deubiquitylating enzymes and disease". BMC Biochemistry. 9 (Suppl 1): S3. doi: 10.1186/1471-2091-9-S1-S3 . PMC   2582804 . PMID   19007433.
  26. ↑ Diefenbacher ME, Popov N, Blake SM, Schülein-Völk C, Nye E, Spencer-Dene B, et al. (August 2014). "The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer". The Journal of Clinical Investigation. 124 (8): 3407–18. doi:10.1172/JCI73733. PMC   4109555 . PMID   24960159.
  27. ↑ Prieto-Garcia C, Hartmann O, Reissland M, Braun F, Fischer T, Walz S, et al. (Jun 2019). "The USP28-∆Np63 axis is a vulnerability of squamous tumours". bioRxiv   10.1101/683508 .
  28. ↑ Prieto-Garcia C, Hartmann O, Reissland M, Braun F, Fischer T, Walz S, et al. (April 2020). "Maintaining protein stability of ∆Np63 via USP28 is required by squamous cancer cells". EMBO Molecular Medicine. 12 (4): e11101. doi:10.15252/emmm.201911101. PMC   7136964 . PMID   32128997.
  29. ↑ Prieto-Garcia C, Hartmann O, Reissland M, Fischer T, Maier CR, Rosenfeldt M, et al. (Sep 2020). "Inhibition of USP28 overcomes Cisplatin-Resistance of Squamous Tumors by Suppression of the Fanconi Anemia Pathway". bioRxiv   10.1101/2020.09.10.291278 .
  30. ↑ Dennissen FJ, Kholod N, Hermes DJ, Kemmerling N, Steinbusch HW, Dantuma NP, van Leeuwen FW (August 2011). "Mutant ubiquitin (UBB+1) associated with neurodegenerative disorders is hydrolyzed by ubiquitin C-terminal hydrolase L3 (UCH-L3)". FEBS Letters. 585 (16): 2568–74. doi: 10.1016/j.febslet.2011.06.037 . PMID   21762696. S2CID   28207136.
  31. ↑ Fang Y, Fu D, Shen XZ (August 2010). "The potential role of ubiquitin c-terminal hydrolases in oncogenesis". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1806 (1): 1–6. doi:10.1016/j.bbcan.2010.03.001. PMID   20302916.
  32. ↑ Valles GJ, Bezsonova I, Woodgate R, Ashton NW (August 2020). "USP7 Is a Master Regulator of Genome Stability". Frontiers in Cell and Developmental Biology. 8 (717): 717. doi: 10.3389/fcell.2020.00717 . PMC   7419626 . PMID   32850836.
  33. ↑ Fukuura K, Inoue Y, Miyajima C, Watanabe S, Tokugawa M, Morishita D, et al. (November 2019). "The ubiquitin-specific protease USP17 prevents cellular senescence by stabilizing the methyltransferase SET8 and transcriptionally repressing p21". The Journal of Biological Chemistry. 294 (44): 16429–16439. doi: 10.1074/jbc.RA119.009006 . PMC   6827320 . PMID   31533987.
  34. 1 2 3 4 5 6 Ducker C, Shaw PE (January 2021). "USP17-mediated de-ubiquitination and cancer: Clients cluster around the cell cycle" (PDF). The International Journal of Biochemistry & Cell Biology. 130 (130): 105886. doi: 10.1016/j.biocel.2020.105886 . ISSN   1357-2725. PMID   33227393. S2CID   227158810.
  35. 1 2 3 4 5 Stegmeier F, Rape M, Draviam VM, Nalepa G, Sowa ME, Ang XL, et al. (April 2007). "Anaphase initiation is regulated by antagonistic ubiquitination and deubiquitination activities". Nature. 446 (7138): 876–81. Bibcode:2007Natur.446..876S. doi:10.1038/nature05694. PMID   17443180. S2CID   4321083.
  36. ↑ Karlsson C, Akula MK, Staffas A, Cisowski J, Sayin VI, Ibrahim MX, et al. (February 2021). "Knockout of the RAS endoprotease RCE1 accelerates myeloid leukemia by downregulating GADD45b". Leukemia. 35 (2): 606–609. doi:10.1038/s41375-020-0859-0. PMID   32398789. S2CID   218605961.
  37. ↑ Braun BS, Shannon K (April 2008). "Targeting Ras in myeloid leukemias". Clinical Cancer Research. 14 (8): 2249–52. doi: 10.1158/1078-0432.CCR-07-1005 . PMID   18413813.
  38. ↑ Shen T, Huang S (July 2012). "The role of Cdc25A in the regulation of cell proliferation and apoptosis". Anti-Cancer Agents in Medicinal Chemistry. 12 (6): 631–9. doi:10.2174/187152012800617678. PMC   3544488 . PMID   22263797.
  39. ↑ David R (December 2010). "Cell cycle: Disposing of SETD8". Nature Reviews. Molecular Cell Biology. 11 (12): 819. doi: 10.1038/nrm3020 . PMID   21102605. S2CID   30122715.
  40. 1 2 Liu ST, Zhang H (October 2016). "The mitotic checkpoint complex (MCC): looking back and forth after 15 years". AIMS Molecular Science. 3 (4): 597–634. doi:10.3934/molsci.2016.4.597. PMC   5597056 . PMID   28920074.
  41. ↑ Potapova T, Gorbsky GJ (February 2017). "The Consequences of Chromosome Segregation Errors in Mitosis and Meiosis". Biology. 6 (1): 12. doi: 10.3390/biology6010012 . PMC   5372005 . PMID   28208750.
  42. ↑ Wirth KG, Ricci R, Giménez-Abián JF, Taghybeeglu S, Kudo NR, Jochum W, et al. (January 2004). "Loss of the anaphase-promoting complex in quiescent cells causes unscheduled hepatocyte proliferation". Genes & Development. 18 (1): 88–98. doi:10.1101/gad.285404. PMC   314282 . PMID   14724179.
  43. 1 2 Fang G, Yu H, Kirschner MW (June 1998). "The checkpoint protein MAD2 and the mitotic regulator CDC20 form a ternary complex with the anaphase-promoting complex to control anaphase initiation". Genes & Development. 12 (12): 1871–83. doi:10.1101/gad.12.12.1871. PMC   316912 . PMID   9637688.
  44. ↑ Peters JM (April 2007). "Cell biology: the checkpoint brake relieved". Nature. 446 (7138): 868–9. Bibcode:2007Natur.446..868P. doi: 10.1038/446868a . PMID   17443175.
  45. ↑ "TP53 gene". MedlinePlus. U.S. National Library of Medicine. Retrieved May 18, 2021.
  46. ↑ "p53". Wikipedia. Retrieved May 18, 2021.
  47. ↑ Li M, Chen D, Shiloh A, Luo J, Nikolaev AY, Qin J, Gu W (April 2002). "Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization". Nature. 416 (6881): 648–53. Bibcode:2002Natur.416..648L. doi:10.1038/nature737. PMID   11923872. S2CID   4389394.
  48. 1 2 Fernández-Montalván A, Bouwmeester T, Joberty G, Mader R, Mahnke M, Pierrat B, et al. (August 2007). "Biochemical characterization of USP7 reveals post-translational modification sites and structural requirements for substrate processing and subcellular localization". The FEBS Journal. 274 (16): 4256–70. doi: 10.1111/j.1742-4658.2007.05952.x . PMID   17651432.
  49. 1 2 Donehower LA (May 2014). "Phosphatases reverse p53-mediated cell cycle checkpoints". Proceedings of the National Academy of Sciences of the United States of America. 111 (20): 7172–3. Bibcode:2014PNAS..111.7172D. doi: 10.1073/pnas.1405663111 . PMC   4034213 . PMID   24808140.
  50. 1 2 3 Chen L, Liu S, Tao Y (June 2020). "Regulating tumor suppressor genes: post-translational modifications". Signal Transduction and Targeted Therapy. 5 (1): 90. doi:10.1038/s41392-020-0196-9. PMC   7293209 . PMID   32532965.
This article incorporates text from the public domain Pfam and InterPro: IPR006615
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.