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Protein

Ubiquitin carboxyl-terminal hydrolase 28

Gene

USP28

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Deubiquitinase involved in DNA damage response checkpoint and MYC proto-oncogene stability. Involved in DNA damage induced apoptosis by specifically deubiquitinating proteins of the DNA damage pathway such as CLSPN. Also involved in G2 DNA damage checkpoint, by deubiquitinating CLSPN, and preventing its degradation by the anaphase promoting complex/cyclosome (APC/C). In contrast, it does not deubiquitinate PLK1. Specifically deubiquitinates MYC in the nucleoplasm, leading to prevent MYC degradation by the proteasome: acts by specifically interacting with isoform 1 of FBXW7 (FBW7alpha) in the nucleoplasm and counteracting ubiquitination of MYC by the SCF(FBW7) complex. In contrast, it does not interact with isoform 4 of FBXW7 (FBW7gamma) in the nucleolus, allowing MYC degradation and explaining the selective MYC degradation in the nucleolus. Deubiquitinates ZNF304, hence preventing ZNF304 degradation by the proteasome and leading to the activated KRAS-mediated promoter hypermethylation and transcriptional silencing of tumor suppressor genes (TSGs) in a subset of colorectal cancers (CRC) cells (PubMed:24623306).5 Publications

Catalytic activityi

Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei171Nucleophile1
Active sitei600Proton acceptorPROSITE-ProRule annotation1

GO - Molecular functioni

  • thiol-dependent ubiquitin-specific protease activity Source: UniProtKB
  • thiol-dependent ubiquitinyl hydrolase activity Source: UniProtKB

GO - Biological processi

Keywordsi

Molecular functionHydrolase, Protease, Thiol protease
Biological processDNA damage, DNA repair, Ubl conjugation pathway

Enzyme and pathway databases

ReactomeiR-HSA-5689880 Ub-specific processing proteases
SIGNORiQ96RU2

Protein family/group databases

MEROPSiC19.054

Names & Taxonomyi

Protein namesi
Recommended name:
Ubiquitin carboxyl-terminal hydrolase 28 (EC:3.4.19.12)
Alternative name(s):
Deubiquitinating enzyme 28
Ubiquitin thioesterase 28
Ubiquitin-specific-processing protease 28
Gene namesi
Name:USP28
Synonyms:KIAA1515
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 11

Organism-specific databases

EuPathDBiHostDB:ENSG00000048028.11
HGNCiHGNC:12625 USP28
MIMi610748 gene
neXtProtiNX_Q96RU2

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi171C → A: Abolishes deubiquitinase activity. 3 Publications1
Mutagenesisi899S → A: Prevents ZNF304 ubiquitination reduction. 1 Publication1

Organism-specific databases

DisGeNETi57646
OpenTargetsiENSG00000048028
PharmGKBiPA37250

Chemistry databases

ChEMBLiCHEMBL2157853

Polymorphism and mutation databases

BioMutaiUSP28
DMDMi20140700

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000806571 – 1077Ubiquitin carboxyl-terminal hydrolase 28Add BLAST1077

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei67Phosphoserine1 Publication1
Cross-linki99Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
Modified residuei375PhosphoserineCombined sources1
Modified residuei550PhosphoserineBy similarity1
Modified residuei714Phosphoserine1 Publication1
Modified residuei1048PhosphothreonineCombined sources1
Isoform 2 (identifier: Q96RU2-2)
Cross-linki759Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources

Post-translational modificationi

Degraded upon nickel ion level or hypoxia exposure.
Phosphorylated upon DNA damage at Ser-67 and Ser-714, by ATM or ATR (PubMed:16901786). Phosphorylated by PRKD1 (PubMed:24623306).2 Publications

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ96RU2
MaxQBiQ96RU2
PaxDbiQ96RU2
PeptideAtlasiQ96RU2
PRIDEiQ96RU2
ProteomicsDBi78033
78034 [Q96RU2-2]

PTM databases

iPTMnetiQ96RU2
PhosphoSitePlusiQ96RU2

Expressioni

Inductioni

Down-regulated upon hypoxia (PubMed:20046830). Up-regulated by the transcription factor c-Jun/JUN in a KRAS-dependent manner in colorectal cancer (CRC) cells (PubMed:24623306).2 Publications

Gene expression databases

BgeeiENSG00000048028 Expressed in 193 organ(s), highest expression level in heart
CleanExiHS_USP28
ExpressionAtlasiQ96RU2 baseline and differential
GenevisibleiQ96RU2 HS

Organism-specific databases

HPAiHPA006778
HPA006779

Interactioni

Subunit structurei

Interacts with ZNF304 (PubMed:24623306). Interacts with PRKD1 (PubMed:24623306). Interacts with TP53BP1 (PubMed:16901786). Interacts with isoform 1 of FBXW7; following DNA damage, dissociates from FBXW7 leading to degradation of MYC (PubMed:17873522, PubMed:17558397).4 Publications

Protein-protein interaction databases

BioGridi121683, 71 interactors
IntActiQ96RU2, 12 interactors
MINTiQ96RU2
STRINGi9606.ENSP00000003302

Structurei

Secondary structure

11077
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ96RU2
SMRiQ96RU2
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini97 – 116UIMCuratedAdd BLAST20
Domaini162 – 650USPAdd BLAST489

Sequence similaritiesi

Belongs to the peptidase C19 family. USP28 subfamily.Curated

Phylogenomic databases

eggNOGiKOG1863 Eukaryota
COG5077 LUCA
GeneTreeiENSGT00390000016082
HOGENOMiHOG000007956
HOVERGENiHBG056030
InParanoidiQ96RU2
KOiK21122
OMAiCIASTTQ
OrthoDBiEOG091G00QR
PhylomeDBiQ96RU2
TreeFamiTF329035

Family and domain databases

InterProiView protein in InterPro
IPR038765 Papain_like_cys_pep_sf
IPR001394 Peptidase_C19_UCH
IPR009060 UBA-like_sf
IPR018200 USP_CS
IPR028889 USP_dom
PfamiView protein in Pfam
PF00443 UCH, 1 hit
SUPFAMiSSF46934 SSF46934, 1 hit
SSF54001 SSF54001, 2 hits
PROSITEiView protein in PROSITE
PS00972 USP_1, 1 hit
PS00973 USP_2, 1 hit
PS50235 USP_3, 1 hit

Sequences (3+)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 3 described isoforms and 11 potential isoforms that are computationally mapped.iShow all

Isoform 1 (identifier: Q96RU2-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide
        10         20         30         40         50
MTAELQQDDA AGAADGHGSS CQMLLNQLRE ITGIQDPSFL HEALKASNGD
60 70 80 90 100
ITQAVSLLTD ERVKEPSQDT VATEPSEVEG SAANKEVLAK VIDLTHDNKD
110 120 130 140 150
DLQAAIALSL LESPKIQADG RDLNRMHEAT SAETKRSKRK RCEVWGENPN
160 170 180 190 200
PNDWRRVDGW PVGLKNVGNT CWFSAVIQSL FQLPEFRRLV LSYSLPQNVL
210 220 230 240 250
ENCRSHTEKR NIMFMQELQY LFALMMGSNR KFVDPSAALD LLKGAFRSSE
260 270 280 290 300
EQQQDVSEFT HKLLDWLEDA FQLAVNVNSP RNKSENPMVQ LFYGTFLTEG
310 320 330 340 350
VREGKPFCNN ETFGQYPLQV NGYRNLDECL EGAMVEGDVE LLPSDHSVKY
360 370 380 390 400
GQERWFTKLP PVLTFELSRF EFNQSLGQPE KIHNKLEFPQ IIYMDRYMYR
410 420 430 440 450
SKELIRNKRE CIRKLKEEIK ILQQKLERYV KYGSGPARFP LPDMLKYVIE
460 470 480 490 500
FASTKPASES CPPESDTHMT LPLSSVHCSV SDQTSKESTS TESSSQDVES
510 520 530 540 550
TFSSPEDSLP KSKPLTSSRS SMEMPSQPAP RTVTDEEINF VKTCLQRWRS
560 570 580 590 600
EIEQDIQDLK TCIASTTQTI EQMYCDPLLR QVPYRLHAVL VHEGQANAGH
610 620 630 640 650
YWAYIYNQPR QSWLKYNDIS VTESSWEEVE RDSYGGLRNV SAYCLMYIND
660 670 680 690 700
KLPYFNAEAA PTESDQMSEV EALSVELKHY IQEDNWRFEQ EVEEWEEEQS
710 720 730 740 750
CKIPQMESST NSSSQDYSTS QEPSVASSHG VRCLSSEHAV IVKEQTAQAI
760 770 780 790 800
ANTARAYEKS GVEAALSEVM LSPAMQGVIL AIAKARQTFD RDGSEAGLIK
810 820 830 840 850
AFHEEYSRLY QLAKETPTSH SDPRLQHVLV YFFQNEAPKR VVERTLLEQF
860 870 880 890 900
ADKNLSYDER SISIMKVAQA KLKEIGPDDM NMEEYKKWHE DYSLFRKVSV
910 920 930 940 950
YLLTGLELYQ KGKYQEALSY LVYAYQSNAA LLMKGPRRGV KESVIALYRR
960 970 980 990 1000
KCLLELNAKA ASLFETNDDH SVTEGINVMN ELIIPCIHLI INNDISKDDL
1010 1020 1030 1040 1050
DAIEVMRNHW CSYLGQDIAE NLQLCLGEFL PRLLDPSAEI IVLKEPPTIR
1060 1070
PNSPYDLCSR FAAVMESIQG VSTVTVK
Length:1,077
Mass (Da):122,491
Last modified:December 1, 2001 - v1
Checksum:i799C758888C67B82
GO
Isoform 2 (identifier: Q96RU2-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     769-800: Missing.

Show »
Length:1,045
Mass (Da):119,121
Checksum:i1A10819BCF8CCBC6
GO
Isoform 3 (identifier: Q96RU2-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     583-583: P → E
     584-1077: Missing.

Note: No experimental confirmation available.
Show »
Length:583
Mass (Da):66,243
Checksum:iA932AD8856535EBD
GO

Computationally mapped potential isoform sequencesi

There are 11 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
B4E3L3B4E3L3_HUMAN
Ubiquitin carboxyl-terminal hydrola...
USP28
920Annotation score:
G3V1N5G3V1N5_HUMAN
Ubiquitin carboxyl-terminal hydrola...
USP28 hCG_39594
753Annotation score:
H0YG96H0YG96_HUMAN
Ubiquitin carboxyl-terminal hydrola...
USP28
360Annotation score:
H0YFX3H0YFX3_HUMAN
Ubiquitin carboxyl-terminal hydrola...
USP28
244Annotation score:
F5GZ74F5GZ74_HUMAN
Ubiquitin carboxyl-terminal hydrola...
USP28
194Annotation score:
F5H6Q3F5H6Q3_HUMAN
Ubiquitin carboxyl-terminal hydrola...
USP28
46Annotation score:
F5H2G4F5H2G4_HUMAN
Ubiquitin carboxyl-terminal hydrola...
USP28
77Annotation score:
H0YFT9H0YFT9_HUMAN
Ubiquitin carboxyl-terminal hydrola...
USP28
194Annotation score:
H0YFD7H0YFD7_HUMAN
Ubiquitin carboxyl-terminal hydrola...
USP28
51Annotation score:
H0YH19H0YH19_HUMAN
Ubiquitin carboxyl-terminal hydrola...
USP28
91Annotation score:
There is more potential isoformShow all

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti289 – 303VQLFY…EGVRE → IVIVMSFLKSLSLCL in BAA96039 (Ref. 4) CuratedAdd BLAST15

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_057359583P → E in isoform 3. 1 Publication1
Alternative sequenceiVSP_057360584 – 1077Missing in isoform 3. 1 PublicationAdd BLAST494
Alternative sequenceiVSP_015580769 – 800Missing in isoform 2. 1 PublicationAdd BLAST32

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF266283 mRNA Translation: AAK58565.1
EF445045 Genomic DNA Translation: ACA06098.1
EF445045 Genomic DNA Translation: ACA06099.1
AP001874 Genomic DNA No translation available.
AP003170 Genomic DNA No translation available.
KF455523 Genomic DNA No translation available.
KF459544 Genomic DNA No translation available.
CH471065 Genomic DNA Translation: EAW67232.1
BC065928 mRNA Translation: AAH65928.1
AB040948 mRNA Translation: BAA96039.1
CCDSiCCDS31680.1 [Q96RU2-1]
CCDS86248.1 [Q96RU2-3]
RefSeqiNP_001333187.1, NM_001346258.1 [Q96RU2-2]
NP_001333202.1, NM_001346273.1 [Q96RU2-3]
NP_065937.1, NM_020886.3 [Q96RU2-1]
UniGeneiHs.503891

Genome annotation databases

EnsembliENST00000003302; ENSP00000003302; ENSG00000048028 [Q96RU2-1]
ENST00000537706; ENSP00000445743; ENSG00000048028 [Q96RU2-3]
GeneIDi57646
KEGGihsa:57646
UCSCiuc001poh.4 human [Q96RU2-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiUBP28_HUMAN
AccessioniPrimary (citable) accession number: Q96RU2
Secondary accession number(s): B0YJC0
, B0YJC1, Q6NZX9, Q9P213
Entry historyiIntegrated into UniProtKB/Swiss-Prot: March 27, 2002
Last sequence update: December 1, 2001
Last modified: September 12, 2018
This is version 158 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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