P35123 (UBP4_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Ubiquitin carboxyl-terminal hydrolase 4
EC=3.4.19.12

Alternative name(s):
Deubiquitinating enzyme 4
Ubiquitin thioesterase 4
Ubiquitin-specific-processing protease 4
Ubiquitous nuclear protein

Gene names

Name:	Usp4
Synonyms:	Unp

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	962 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Hydrolase that deubiquitinates target proteins such as the receptor ADORA2A, PDPK1 and TRIM21. Deubiquitination of ADORA2A increases the amount of functional receptor at the cell surface. Plays a role in the regulation of quality control in the ER By similarity.
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 RB1 (both dephosphorylated and hypophosphorylated forms). Interacts with ADORA2A (via cytoplasmic C-terminus); the interaction is direct By similarity. Interacts with RB1, RBL1 and RBL2. Ref.5
Subcellular location	Cytoplasm. Nucleus. Note: Shuttles between the nucleus and cytoplasm. Exported to the cytoplasm in a CRM1-dependent manner and recycled back to the nucleus via the importin alpha/beta heterodimeric import receptor. Ref.6
Tissue specificity	Expressed in brain, kidney, liver and spleen (at protein level). Ref.6
Developmental stage	Overexpression leads to oncogenic transformation of NIH 3T3 cells.
Domain	The Ubiquitin-like domain 2 inserts into the catalytic domain and competes with the ubiquitin substrate, partially inhibiting DUB activity By similarity.
Post-translational modification	Monoubiquitinated by TRIM21. Ubiquitination does not lead to its proteasomal degradation. Autodeubiquitinated By similarity.
Sequence similarities	Belongs to the peptidase C19 family. USP4 subfamily. Contains 1 DUSP domain. Contains 2 ubiquitin-like domains.

Ontologies

Keywords
Biological process	Ubl conjugation pathway
Cellular component	Cytoplasm Nucleus
Disease	Proto-oncogene
Domain	Repeat
Ligand	Metal-binding Zinc
Molecular function	Hydrolase Protease Thiol protease
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	negative regulation of protein ubiquitination Inferred from sequence or structural similarity. Source: UniProtKB protein deubiquitination Inferred from sequence or structural similarity. Source: UniProtKB protein localization to cell surface Inferred from sequence or structural similarity. Source: UniProtKB regulation of protein stability Inferred from sequence or structural similarity. Source: UniProtKB ubiquitin-dependent protein catabolic process Inferred from electronic annotation. Source: InterPro
Cellular_component	cytoplasm Inferred from sequence or structural similarity. Source: UniProtKB nucleus Inferred from sequence or structural similarity. Source: UniProtKB
Molecular_function	metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW ubiquitin thiolesterase activity Inferred from sequence or structural similarity. Source: UniProtKB ubiquitin-specific protease activity Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 962

962

Ubiquitin carboxyl-terminal hydrolase 4

PRO_0000080622

Regions

Domain

11 – 122

112

DUSP

Domain

142 – 226

85

Ubiquitin-like 1

Domain

483 – 571

89

Ubiquitin-like 2

Region

405 – 407

3

Necessary for interaction with RBL2

Region

459 – 463

5

Necessary for interaction with RB1 and RBL2

Motif

133 – 141

9

Nuclear export signal

Motif

766 – 771

6

Nuclear localization signal

Sites

Active site

311

1

Nucleophile By similarity

Active site

880

1

Proton acceptor By similarity

Metal binding

461

1

Zinc By similarity

Metal binding

464

1

Zinc By similarity

Metal binding

798

1

Zinc By similarity

Metal binding

801

1

Zinc By similarity

Amino acid modifications

Modified residue

680

1

Phosphoserine Ref.7

Experimental info

Mutagenesis

461

1

C → Q: Reduces the interaction with RB1. Ref.5

Mutagenesis

770 – 771

2

KK → NS: Reduces nuclear localization. Ref.6

Sequence conflict

123 – 124

2

EH → DD in AAB82339. Ref.1

Sequence conflict

123 – 124

2

EH → DD in AAC53587. Ref.2

Sequence conflict

292

1

P → A in AAB82339. Ref.1

Secondary structure

1

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962

Helix Strand Turn

Details...

Helix

13 – 21

9

Turn

22 – 25

4

Beta strand

33 – 38

6

Helix

39 – 49

11

Beta strand

51 – 53

3

Turn

56 – 60

5

Helix

62 – 64

3

Helix

72 – 74

3

Beta strand

75 – 77

3

Turn

78 – 81

4

Turn

89 – 91

3

Beta strand

92 – 97

6

Helix

98 – 108

11

Beta strand

118 – 124

7

Beta strand

126 – 128

3

Beta strand

130 – 133

4

Beta strand

138 – 144

7

Beta strand

147 – 156

10

Helix

162 – 172

11

Beta strand

181 – 185

5

Beta strand

187 – 191

5

Turn

202 – 206

5

Beta strand

211 – 217

7

Sequences

	Sequence		Length	Mass (Da)
	P35123 [UniParc]. Last modified July 27, 2011. Version 3. Checksum: 95F95BE86186DA52	FASTA	962	108,343
	10 20 30 40 50 60 MAEGRGSRER PDVETQKTEL GALMGTTLQR GAQWYLIDSR WFKQWKKYVG FDSWDMYNVG 70 80 90 100 110 120 EHNLFPGPID NSGLFSDPES QTLKEHLIDE LDYVLVPAEA WNKLLNWYGC VEGQQPIVRK 130 140 150 160 170 180 VVEHGLFVKH CKVEVYLLEL KLCENSDPTN VLSCHFSKAD TIATIEKEMR KLFNIPAERE 190 200 210 220 230 240 TRLWNKYMSN TYEQLSKLDN TIQDAGLYQG QVLVIEPQNE DGTWPRQSLQ SKSSTAPSRN 250 260 270 280 290 300 FTTSSKPSAS PYCSVSASLI ANGDSTNSSG MHSSGVSRGG SGFSASYNCQ EPPSPHIQPG 310 320 330 340 350 360 LCGLGNLGNT CFMNSALQCL SNTAPLTEYF LKDEYEAEIN RDNPLGMKGE IAEAYAELIK 370 380 390 400 410 420 QMWSGRDTHV APRMFKTQVG RFAPQFSGYQ QQDSQELLAF ILDGLHEDLN RVKKKPYLEP 430 440 450 460 470 480 KDANGRPDAV VAKEAWENHR LRNDSVIVDT FHGLFKSTLV CPECAKVSVT FDPFCYLTLP 490 500 510 520 530 540 LPLKKDRIME VFLVPADPQC RPIQYRVTVP LMGAISDLCE ALSKLSGIAA ENMVVTDVYN 550 560 570 580 590 600 HRFHKIFQMD EGLSHITPRD DIFVYEVCNT SMDGSECITL PVYFREKKSR PSSASSGAVL 610 620 630 640 650 660 YGQPLLVSVP KHKLTLESLY QAVCDRISRY IKQPLPDEFL SSPLEPGACN GSRSSYEGDE 670 680 690 700 710 720 EEEMDHQEEG KEQLSEVEGS GEDDQGDDHS ESAQKVKGQP RHKRLFTFSL VNSCGTADIN 730 740 750 760 770 780 SLATDGKLLK LNSRSTLAID WDSETRSLYF DEQESEACEK HLSMSQPQKK KKAAVALREC 790 800 810 820 830 840 IELFTTMETL GEHDPWYCPT CKKHQQATKK FDLWSLPKIL VVHLKRFSYN RYWRDKLDTV 850 860 870 880 890 900 VEFPVRALNM SEFVCDRSAR PYVYDLIAVS NHYGAMGVGH YTAYAKNRLN GKWYYFDDSS 910 920 930 940 950 960 VSLASEDQIV TKAAYVLFYQ RRDDECSSTS SLGSFPGSDG GVKLSSSHQG MGDEEAYNMD TN

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Unp, a mouse gene related to the tre oncogene." Gupta K., Copeland N.G., Gilbert D.J., Jenkins N.A., Gray D.A. Oncogene 8:2307-2310(1993) [PubMed] [Europe PMC] [Abstract] Cited for: PRELIMINARY NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Genomic structure of Unp, a murine gene encoding a ubiquitin-specific protease." di Fruscio M., Gilchrist C.A., Baker R.T., Gray D.A. Biochim. Biophys. Acta 1398:9-17(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Strain: 129. Tissue: Testis.
[3]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: C57BL/6J and NOD. Tissue: Bone marrow and Spleen.
[4]	Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"Association of UNP, a ubiquitin-specific protease, with the pocket proteins pRb, p107 and p130." Blanchette P., Gilchrist C.A., Baker R.T., Gray D.A. Oncogene 20:5533-5537(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH RB1; RBL1 AND RBL2, MUTAGENESIS OF CYS-461.
[6]	"Nuclear-cytoplasmic shuttling of the oncogenic mouse UNP/USP4 deubiquitylating enzyme." Soboleva T.A., Jans D.A., Johnson-Saliba M., Baker R.T. J. Biol. Chem. 280:745-752(2005) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF 770-GLN--LYS-771, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[7]	"Solid tumor proteome and phosphoproteome analysis by high resolution mass spectrometry." Zanivan S., Gnad F., Wickstroem S.A., Geiger T., Macek B., Cox J., Faessler R., Mann M. J. Proteome Res. 7:5314-5326(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-680, MASS SPECTROMETRY. Tissue: Melanoma.
[8]	"Crystal structure of the N-terminal domains of the ubiquitin specific peptidase 4 (USP4)." Structural genomics consortium (SGC) Submitted (NOV-2009) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (2.37 ANGSTROMS) OF 1-229.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L00681 mRNA. Translation: AAB82339.1.
AF026469 Genomic DNA. Translation: AAC53587.1.
AK089425 mRNA. Translation: BAC40877.1.
AK143582 mRNA. Translation: BAE25450.1.
AK149964 mRNA. Translation: BAE29198.1.
AK169933 mRNA. Translation: BAE41468.1.
AK171271 mRNA. Translation: BAE42357.1.
CH466560 Genomic DNA. Translation: EDL21282.1.

IPI

IPI00115701.

PIR

I58376.

RefSeq

NP_035808.2. NM_011678.2.

UniGene

Mm.3974.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3JYU	X-ray	2.37	A/B	1-229	[»]

ProteinModelPortal

P35123.

SMR

P35123. Positions 7-226, 297-483, 775-924.

ModBase

Search...

Protein family/group databases

MEROPS

C19.010.

PTM databases

PhosphoSite

P35123.

Proteomic databases

PaxDb

P35123.

PRIDE

P35123.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENSMUST00000035237; ENSMUSP00000035237; ENSMUSG00000032612.

GeneID

22258.

KEGG

mmu:22258.

Organism-specific databases

CTD

7375.

MGI

MGI:98905. Usp4.

Phylogenomic databases

eggNOG

COG5560.

GeneTree

ENSGT00670000097750.

HOGENOM

HOG000264375.

HOVERGEN

HBG000864.

InParanoid

Q8BTL9.

KO

K11835.

OMA

CERISRY.

OrthoDB

EOG4C5CHR.

Gene expression databases

ArrayExpress

P35123.

Bgee

P35123.

CleanEx

MM_USP4.

Genevestigator

P35123.

GermOnline

ENSMUSG00000032612. Mus musculus.

Family and domain databases

InterPro

IPR006615. Pept_C19_DUSP.
IPR018200. Pept_C19ubi-hydrolase_C_CS.
IPR001394. Peptidase_C19.
[Graphical view]

Pfam

PF06337. DUSP. 1 hit.
PF00443. UCH. 1 hit.
[Graphical view]

SMART

SM00695. DUSP. 1 hit.
[Graphical view]

PROSITE

PS51283. DUSP. 1 hit.
PS00299. UBIQUITIN_1. False negative.
PS50053. UBIQUITIN_2. False negative.
PS00972. UCH_2_1. 1 hit.
PS00973. UCH_2_2. 1 hit.
PS50235. UCH_2_3. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

P35123.

NextBio

302345.

SOURCE

Search...

Entry information

Entry name

UBP4_MOUSE

Accession

Primary (citable) accession number: P35123
Secondary accession number(s): O54704, Q8BTL9

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1994
Last sequence update:	July 27, 2011
Last modified:	April 3, 2013
This is version 110 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program