Q96RU2 (UBP28_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:	USP28
Synonyms:	KIAA1515

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	1077 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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. Ref.6 Ref.7 Ref.8 Ref.10
Catalytic activity	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).
Subunit structure	Interacts with isoform 1 of FBXW7; following DNA damage, dissociates from FBXW7 leading to degradation of MYC. Ref.6 Ref.7 Ref.8
Subcellular location	Nucleus › nucleoplasm Ref.8.
Induction	Down-regulated upon hypoxia. Ref.11
Post-translational modification	Degradaded upon nickel ion level or hypoxia exposure. Phosphorylated upon DNA damage at Ser-67 and Ser-714, by ATM or ATR. Ref.6
Sequence similarities	Belongs to the peptidase C19 family. USP28 subfamily. Contains 1 UIM (ubiquitin-interacting motif) repeat.

Ontologies

Keywords
Biological process	DNA damage DNA repair Ubl conjugation pathway
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing
Molecular function	Hydrolase Protease Thiol protease
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	DNA damage checkpoint Inferred from mutant phenotype Ref.10. Source: UniProtKB DNA repair Inferred from electronic annotation. Source: UniProtKB-KW cell proliferation Inferred from mutant phenotype Ref.8. Source: UniProtKB cellular response to UV Inferred from direct assay Ref.7. Source: UniProtKB intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator Inferred from direct assay Ref.6. Source: UniProtKB protein deubiquitination Inferred from direct assay Ref.6Ref.8Ref.10. Source: UniProtKB response to ionizing radiation Inferred from direct assay Ref.6. Source: UniProtKB ubiquitin-dependent protein catabolic process Inferred from electronic annotation. Source: InterPro
Cellular_component	nucleolus Inferred from direct assay. Source: HPA nucleoplasm Inferred from direct assay Ref.8. Source: UniProtKB protein complex Inferred from direct assay Ref.7. Source: UniProtKB
Molecular_function	ubiquitin thiolesterase activity Inferred from mutant phenotype Ref.6Ref.8. Source: UniProtKB ubiquitin-specific protease activity Inferred from direct assay Ref.6Ref.8. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q96RU2-1)

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.

Isoform 2 (identifier: Q96RU2-2)

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

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 1077

1077

Ubiquitin carboxyl-terminal hydrolase 28

PRO_0000080657

Regions

Repeat

97 – 116

20

UIM

Sites

Active site

171

1

Nucleophile

Active site

600

1

Proton acceptor By similarity

Amino acid modifications

Modified residue

67

1

Phosphoserine Ref.6

Modified residue

714

1

Phosphoserine Ref.6

Natural variations

Alternative sequence

769 – 800

32

Missing in isoform 2.

VSP_015580

Experimental info

Mutagenesis

171

1

C → A: Abolishes deubiquitinase activity. Ref.6 Ref.8

Sequence conflict

289 – 303

15

VQLFY…EGVRE → IVIVMSFLKSLSLCL in BAA96039. Ref.4

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

1077

Helix Strand Turn

Details...

Helix

23 – 32

10

Helix

37 – 46

10

Turn

47 – 49

3

Helix

51 – 58

8

Helix

60 – 63

4

Helix

100 – 111

12

Helix

121 – 123

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified December 1, 2001. Version 1. Checksum: 799C758888C67B82	FASTA	1,077	122,491
	10 20 30 40 50 60 MTAELQQDDA AGAADGHGSS CQMLLNQLRE ITGIQDPSFL HEALKASNGD ITQAVSLLTD 70 80 90 100 110 120 ERVKEPSQDT VATEPSEVEG SAANKEVLAK VIDLTHDNKD DLQAAIALSL LESPKIQADG 130 140 150 160 170 180 RDLNRMHEAT SAETKRSKRK RCEVWGENPN PNDWRRVDGW PVGLKNVGNT CWFSAVIQSL 190 200 210 220 230 240 FQLPEFRRLV LSYSLPQNVL ENCRSHTEKR NIMFMQELQY LFALMMGSNR KFVDPSAALD 250 260 270 280 290 300 LLKGAFRSSE EQQQDVSEFT HKLLDWLEDA FQLAVNVNSP RNKSENPMVQ LFYGTFLTEG 310 320 330 340 350 360 VREGKPFCNN ETFGQYPLQV NGYRNLDECL EGAMVEGDVE LLPSDHSVKY GQERWFTKLP 370 380 390 400 410 420 PVLTFELSRF EFNQSLGQPE KIHNKLEFPQ IIYMDRYMYR SKELIRNKRE CIRKLKEEIK 430 440 450 460 470 480 ILQQKLERYV KYGSGPARFP LPDMLKYVIE FASTKPASES CPPESDTHMT LPLSSVHCSV 490 500 510 520 530 540 SDQTSKESTS TESSSQDVES TFSSPEDSLP KSKPLTSSRS SMEMPSQPAP RTVTDEEINF 550 560 570 580 590 600 VKTCLQRWRS EIEQDIQDLK TCIASTTQTI EQMYCDPLLR QVPYRLHAVL VHEGQANAGH 610 620 630 640 650 660 YWAYIYNQPR QSWLKYNDIS VTESSWEEVE RDSYGGLRNV SAYCLMYIND KLPYFNAEAA 670 680 690 700 710 720 PTESDQMSEV EALSVELKHY IQEDNWRFEQ EVEEWEEEQS CKIPQMESST NSSSQDYSTS 730 740 750 760 770 780 QEPSVASSHG VRCLSSEHAV IVKEQTAQAI ANTARAYEKS GVEAALSEVM LSPAMQGVIL 790 800 810 820 830 840 AIAKARQTFD RDGSEAGLIK AFHEEYSRLY QLAKETPTSH SDPRLQHVLV YFFQNEAPKR 850 860 870 880 890 900 VVERTLLEQF ADKNLSYDER SISIMKVAQA KLKEIGPDDM NMEEYKKWHE DYSLFRKVSV 910 920 930 940 950 960 YLLTGLELYQ KGKYQEALSY LVYAYQSNAA LLMKGPRRGV KESVIALYRR KCLLELNAKA 970 980 990 1000 1010 1020 ASLFETNDDH SVTEGINVMN ELIIPCIHLI INNDISKDDL DAIEVMRNHW CSYLGQDIAE 1030 1040 1050 1060 1070 NLQLCLGEFL PRLLDPSAEI IVLKEPPTIR PNSPYDLCSR FAAVMESIQG VSTVTVK
	Isoform 2 [UniParc]. Checksum: 1A10819BCF8CCBC6	FASTA	1,045	119,121
	10 20 30 40 50 60 MTAELQQDDA AGAADGHGSS CQMLLNQLRE ITGIQDPSFL HEALKASNGD ITQAVSLLTD 70 80 90 100 110 120 ERVKEPSQDT VATEPSEVEG SAANKEVLAK VIDLTHDNKD DLQAAIALSL LESPKIQADG 130 140 150 160 170 180 RDLNRMHEAT SAETKRSKRK RCEVWGENPN PNDWRRVDGW PVGLKNVGNT CWFSAVIQSL 190 200 210 220 230 240 FQLPEFRRLV LSYSLPQNVL ENCRSHTEKR NIMFMQELQY LFALMMGSNR KFVDPSAALD 250 260 270 280 290 300 LLKGAFRSSE EQQQDVSEFT HKLLDWLEDA FQLAVNVNSP RNKSENPMVQ LFYGTFLTEG 310 320 330 340 350 360 VREGKPFCNN ETFGQYPLQV NGYRNLDECL EGAMVEGDVE LLPSDHSVKY GQERWFTKLP 370 380 390 400 410 420 PVLTFELSRF EFNQSLGQPE KIHNKLEFPQ IIYMDRYMYR SKELIRNKRE CIRKLKEEIK 430 440 450 460 470 480 ILQQKLERYV KYGSGPARFP LPDMLKYVIE FASTKPASES CPPESDTHMT LPLSSVHCSV 490 500 510 520 530 540 SDQTSKESTS TESSSQDVES TFSSPEDSLP KSKPLTSSRS SMEMPSQPAP RTVTDEEINF 550 560 570 580 590 600 VKTCLQRWRS EIEQDIQDLK TCIASTTQTI EQMYCDPLLR QVPYRLHAVL VHEGQANAGH 610 620 630 640 650 660 YWAYIYNQPR QSWLKYNDIS VTESSWEEVE RDSYGGLRNV SAYCLMYIND KLPYFNAEAA 670 680 690 700 710 720 PTESDQMSEV EALSVELKHY IQEDNWRFEQ EVEEWEEEQS CKIPQMESST NSSSQDYSTS 730 740 750 760 770 780 QEPSVASSHG VRCLSSEHAV IVKEQTAQAI ANTARAYEKS GVEAALSEAF HEEYSRLYQL 790 800 810 820 830 840 AKETPTSHSD PRLQHVLVYF FQNEAPKRVV ERTLLEQFAD KNLSYDERSI SIMKVAQAKL 850 860 870 880 890 900 KEIGPDDMNM EEYKKWHEDY SLFRKVSVYL LTGLELYQKG KYQEALSYLV YAYQSNAALL 910 920 930 940 950 960 MKGPRRGVKE SVIALYRRKC LLELNAKAAS LFETNDDHSV TEGINVMNEL IIPCIHLIIN 970 980 990 1000 1010 1020 NDISKDDLDA IEVMRNHWCS YLGQDIAENL QLCLGEFLPR LLDPSAEIIV LKEPPTIRPN 1030 1040 SPYDLCSRFA AVMESIQGVS TVTVK

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Characterization of alternatively spliced products and tissue-specific isoforms of USP28 and USP25." Valero R., Bayes M., Francisca Sanchez-Font M., Gonzalez-Angulo O., Gonzalez-Duarte R., Marfany G. Genome Biol. 2:RESEARCH0043.1-RESEARCH0043.10(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	NHLBI resequencing and genotyping service (RS&G) Submitted (FEB-2007) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"Human chromosome 11 DNA sequence and analysis including novel gene identification." Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G. , Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., Sakaki Y. Nature 440:497-500(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"Prediction of the coding sequences of unidentified human genes. XVII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro." Nagase T., Kikuno R., Ishikawa K., Hirosawa M., Ohara O. DNA Res. 7:143-150(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 289-1077 (ISOFORM 2). Tissue: Brain.
[6]	"A role for the deubiquitinating enzyme USP28 in control of the DNA-damage response." Zhang D., Zaugg K., Mak T.W., Elledge S.J. Cell 126:529-542(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH TP53BP1, PHOSPHORYLATION AT SER-67 AND SER-714, MUTAGENESIS OF CYS-171.
[7]	"Fbw7 and Usp28 regulate myc protein stability in response to DNA damage." Popov N., Herold S., Llamazares M., Schulein C., Eilers M. Cell Cycle 6:2327-2331(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH FBXW7.
[8]	"The ubiquitin-specific protease USP28 is required for MYC stability." Popov N., Wanzel M., Madiredjo M., Zhang D., Beijersbergen R., Bernards R., Moll R., Elledge S.J., Eilers M. Nat. Cell Biol. 9:765-774(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH FBXW7, MUTAGENESIS OF CYS-171.
[9]	"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage." Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J. Science 316:1160-1166(2007) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Embryonic kidney.
[10]	"The Cdc14B-Cdh1-Plk1 axis controls the G2 DNA-damage-response checkpoint." Bassermann F., Frescas D., Guardavaccaro D., Busino L., Peschiaroli A., Pagano M. Cell 134:256-267(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[11]	"Mechanisms of c-myc degradation by nickel compounds and hypoxia." Li Q., Kluz T., Sun H., Costa M. PLoS ONE 4:E8531-E8531(2009) [PubMed] [Europe PMC] [Abstract] Cited for: DEGRADATION, INDUCTION.
[12]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[13]	"NMR solution structure of the N-terminal domain of human USP28." Northeast structural genomics consortium (NESG) Submitted (JUL-2012) to the PDB data bank Cited for: STRUCTURE BY NMR OF 22-132.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

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.
CH471065 Genomic DNA. Translation: EAW67232.1.
AB040948 mRNA. Translation: BAA96039.1.

IPI

IPI00045496.
IPI00103951.

RefSeq

NP_065937.1. NM_020886.2.

UniGene

Hs.503891.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2LVA	NMR	-	A	22-132	[»]

ProteinModelPortal

Q96RU2.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q96RU2. 4 interactions.

STRING

9606.ENSP00000003302.

Protein family/group databases

MEROPS

C19.054.

PTM databases

PhosphoSite

Q96RU2.

Polymorphism databases

DMDM

20140700.

Proteomic databases

PaxDb

Q96RU2.

PRIDE

Q96RU2.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000003302; ENSP00000003302; ENSG00000048028.
ENST00000260188; ENSP00000260188; ENSG00000048028.

GeneID

57646.

KEGG

hsa:57646.

UCSC

uc001poh.3. human.

Organism-specific databases

CTD

57646.

GeneCards

GC11M113668.

HGNC

HGNC:12625. USP28.

HPA

HPA006778.
HPA006779.

MIM

610748. gene.

neXtProt

NX_Q96RU2.

PharmGKB

PA37250.

HUGE

Search...

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG5077.

HOGENOM

HOG000007956.

HOVERGEN

HBG056030.

InParanoid

Q96RU2.

KO

K11849.

OMA

DLNRMHE.

OrthoDB

EOG4WM4T0.

Gene expression databases

ArrayExpress

Q96RU2.

Bgee

Q96RU2.

CleanEx

HS_USP28.

Genevestigator

Q96RU2.

GermOnline

ENSG00000048028. Homo sapiens.

Family and domain databases

InterPro

IPR018200. Pept_C19ubi-hydrolase_C_CS.
IPR001394. Peptidase_C19.
IPR009060. UBA-like.
IPR003903. Ubiquitin-int_motif.
[Graphical view]

Pfam

PF00443. UCH. 1 hit.
[Graphical view]

SMART

SM00726. UIM. 1 hit.
[Graphical view]

SUPFAM

SSF46934. UBA_like. 1 hit.

PROSITE

PS00972. UCH_2_1. 1 hit.
PS00973. UCH_2_2. 1 hit.
PS50235. UCH_2_3. 1 hit.
PS50330. UIM. False negative.
[Graphical view]

ProtoNet

Search...

Other

GenomeRNAi

57646.

NextBio

64378.

SOURCE

Search...

Entry information

Entry name

UBP28_HUMAN

Accession

Primary (citable) accession number: Q96RU2
Secondary accession number(s): B0YJC0, B0YJC1, Q9P213

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 27, 2002
Last sequence update:	December 1, 2001
Last modified:	May 1, 2013
This is version 108 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.