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Protein

Ubiquitin carboxyl-terminal hydrolase 28

Gene

USP28

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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

  • cell proliferation Source: UniProtKB
  • cellular response to DNA damage stimulus Source: UniProtKB
  • cellular response to UV Source: UniProtKB
  • DNA damage checkpoint Source: UniProtKB
  • DNA repair Source: UniProtKB-KW
  • intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator Source: UniProtKB
  • protein deubiquitination Source: UniProtKB
  • Ras protein signal transduction Source: UniProtKB
  • regulation of protein stability Source: UniProtKB
  • response to ionizing radiation Source: UniProtKB
  • ubiquitin-dependent protein catabolic process Source: InterPro

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

HGNCiHGNC:12625. USP28.

Subcellular locationi

GO - Cellular componenti

  • nuclear body Source: HPA
  • nucleoplasm Source: UniProtKB
  • protein complex Source: UniProtKB

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

Degradaded 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.

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.
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) (PubMed:17873522).4 Publications

Protein-protein interaction databases

BioGridi121683. 70 interactors.
IntActiQ96RU2. 11 interactors.
MINTiMINT-8415329.
STRINGi9606.ENSP00000003302.

Structurei

Secondary structure

11077
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi7 – 9Combined sources3
Helixi23 – 32Combined sources10
Helixi37 – 46Combined sources10
Turni47 – 49Combined sources3
Helixi51 – 58Combined sources8
Helixi60 – 63Combined sources4
Beta strandi71 – 73Combined sources3
Turni84 – 86Combined sources3
Beta strandi95 – 97Combined sources3
Helixi100 – 111Combined sources12
Helixi121 – 123Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2LVANMR-A22-132[»]
2MUUNMR-A1-120[»]
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
IPR001394. Peptidase_C19_UCH.
IPR009060. UBA-like.
IPR018200. USP_CS.
IPR028889. USP_dom.
PfamiView protein in Pfam
PF00443. UCH. 1 hit.
SUPFAMiSSF46934. SSF46934. 1 hit.
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

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

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]
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: August 30, 2017
This is version 150 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

Documents

  1. Human chromosome 11
    Human chromosome 11: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. Peptidase families
    Classification of peptidase families and list of entries
  5. SIMILARITY comments
    Index of protein domains and families