P54578 (UBP14_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Ubiquitin carboxyl-terminal hydrolase 14
EC=3.4.19.12

Alternative name(s):
Deubiquitinating enzyme 14
Ubiquitin thioesterase 14
Ubiquitin-specific-processing protease 14

Gene names

Name:	USP14
Synonyms:	TGT

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	494 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Proteasome-associated deubiquitinase which releases ubiquitin from the proteasome targeted ubiquitinated proteins. Ensures the regeneration of ubiquitin at the proteasome. Is a reversibly associated subunit of the proteasome and a large fraction of proteasome-free protein exists within the cell. Required for the degradation of the chemokine receptor CXCR4 which is critical for CXCL12-induced cell chemotaxis. Serves also as a physiological inhibitor of endoplasmic reticulum-associated degradation (ERAD) under the non-stressed condition by inhibiting the degradation of unfolded endoplasmic reticulum proteins via interaction with ERN1. Indispensable for synaptic development and function at neuromuscular junctions (NMJs). Ref.6 Ref.8 Ref.9
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). Ref.15
Subunit structure	Homodimer Potential. Associates with the 26S proteasome. Interacts with FANCC, CXCR4 and ERN1. Ref.4 Ref.8 Ref.9
Subcellular location	Cytoplasm. Cell membrane; Peripheral membrane protein Ref.9.
Sequence similarities	Belongs to the peptidase C19 family. USP14/UBP6 subfamily. Contains 1 ubiquitin-like domain.
Caution	Was originally (Ref.1) thought to be a guanine tRNA-ribosyltransferase.

Ontologies

Keywords
Biological process	Ubl conjugation pathway
Cellular component	Cell membrane Cytoplasm Membrane Proteasome
Molecular function	Hydrolase Protease Thiol protease
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	regulation of chemotaxis Inferred from mutant phenotype Ref.9. Source: UniProtKB regulation of proteasomal protein catabolic process Inferred from mutant phenotype Ref.6. Source: UniProtKB synaptic transmission Inferred from electronic annotation. Source: Compara ubiquitin-dependent protein catabolic process Inferred from electronic annotation. Source: InterPro
Cellular_component	cell surface Inferred from direct assay Ref.9. Source: UniProtKB cytoplasmic membrane-bounded vesicle Inferred from direct assay Ref.9. Source: UniProtKB plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell proteasome complex Inferred from electronic annotation. Source: UniProtKB-KW synapse Inferred from electronic annotation. Source: Compara
Molecular_function	cysteine-type endopeptidase activity Traceable author statement PubMed 9827704. Source: ProtInc endopeptidase inhibitor activity Inferred from mutant phenotype Ref.6. Source: UniProtKB proteasome binding Inferred from direct assay Ref.6. Source: UniProtKB tRNA guanylyltransferase activity Traceable author statement PubMed 8579355. Source: ProtInc ubiquitin thiolesterase activity Inferred from direct assay Ref.9. Source: UniProtKB ubiquitin-specific protease activity Traceable author statement PubMed 8579355. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 494

494

Ubiquitin carboxyl-terminal hydrolase 14

PRO_0000080636

Regions

Domain

4 – 80

77

Ubiquitin-like

Sites

Active site

114

1

Nucleophile Probable

Active site

435

1

Proton acceptor By similarity

Amino acid modifications

Modified residue

136

1

Phosphotyrosine By similarity

Modified residue

143

1

Phosphoserine Ref.5 Ref.10 Ref.12 Ref.14

Modified residue

222

1

Phosphoserine By similarity

Modified residue

235

1

Phosphothreonine Ref.12

Modified residue

449

1

N6-acetyllysine Ref.11

Secondary structure

1

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494

Helix Strand Turn

Details...

Beta strand

110 – 112

3

Helix

114 – 124

11

Helix

127 – 134

8

Beta strand

144 – 147

4

Helix

148 – 166

19

Beta strand

168 – 170

3

Helix

173 – 182

10

Helix

184 – 187

4

Helix

200 – 212

13

Helix

242 – 246

5

Beta strand

249 – 260

12

Beta strand

269 – 278

10

Beta strand

280 – 282

3

Helix

286 – 292

7

Beta strand

297 – 301

5

Turn

303 – 306

4

Beta strand

311 – 319

9

Beta strand

322 – 329

8

Beta strand

336 – 339

4

Beta strand

351 – 354

4

Helix

356 – 358

3

Helix

361 – 366

6

Turn

367 – 371

5

Helix

372 – 374

3

Turn

409 – 412

4

Beta strand

416 – 430

15

Beta strand

433 – 443

11

Beta strand

446 – 451

6

Beta strand

454 – 458

5

Helix

460 – 463

4

Helix

464 – 467

4

Beta strand

468 – 472

5

Beta strand

474 – 481

8

Sequences

	Sequence		Length	Mass (Da)
	P54578 [UniParc]. Last modified January 23, 2007. Version 3. Checksum: E6D4679A86E9DF00	FASTA	494	56,069
	10 20 30 40 50 60 MPLYSVTVKW GKEKFEGVEL NTDEPPMVFK AQLFALTGVQ PARQKVMVKG GTLKDDDWGN 70 80 90 100 110 120 IKIKNGMTLL MMGSADALPE EPSAKTVFVE DMTEEQLASA MELPCGLTNL GNTCYMNATV 130 140 150 160 170 180 QCIRSVPELK DALKRYAGAL RASGEMASAQ YITAALRDLF DSMDKTSSSI PPIILLQFLH 190 200 210 220 230 240 MAFPQFAEKG EQGQYLQQDA NECWIQMMRV LQQKLEAIED DSVKETDSSS ASAATPSKKK 250 260 270 280 290 300 SLIDQFFGVE FETTMKCTES EEEEVTKGKE NQLQLSCFIN QEVKYLFTGL KLRLQEEITK 310 320 330 340 350 360 QSPTLQRNAL YIKSSKISRL PAYLTIQMVR FFYKEKESVN AKVLKDVKFP LMLDMYELCT 370 380 390 400 410 420 PELQEKMVSF RSKFKDLEDK KVNQQPNTSD KKSSPQKEVK YEPFSFADDI GSNNCGYYDL 430 440 450 460 470 480 QAVLTHQGRS SSSGHYVSWV KRKQDEWIKF DDDKVSIVTP EDILRLSGGG DWHIAYVLLY 490 GPRRVEIMEE ESEQ

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"tRNA-guanine transglycosylase cDNA from human placenta." Deshpande K.L., Katze J.R. Submitted (AUG-1995) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Placenta.
[2]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Skin.
[4]	"Yeast two-hybrid screens imply involvement of Fanconi anemia proteins in transcription regulation, cell signaling, oxidative metabolism, and cellular transport." Reuter T.Y., Medhurst A.L., Waisfisz Q., Zhi Y., Herterich S., Hoehn H., Gross H.J., Joenje H., Hoatlin M.E., Mathew C.G., Huber P.A. Exp. Cell Res. 289:211-221(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH FANCC.
[5]	"Phosphorylation analysis of primary human T lymphocytes using sequential IMAC and titanium oxide enrichment." Carrascal M., Ovelleiro D., Casas V., Gay M., Abian J. J. Proteome Res. 7:5167-5176(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-143, MASS SPECTROMETRY. Tissue: T-cell.
[6]	"Relative structural and functional roles of multiple deubiquitylating proteins associated with mammalian 26S proteasome." Koulich E., Li X., DeMartino G.N. Mol. Biol. Cell 19:1072-1082(2008) [PubMed] [Europe PMC] [Abstract] Cited for: ASSOCIATION WITH THE 26S PROTEASOME, FUNCTION.
[7]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[8]	"USP14 inhibits ER-associated degradation via interaction with IRE1alpha." Nagai A., Kadowaki H., Maruyama T., Takeda K., Nishitoh H., Ichijo H. Biochem. Biophys. Res. Commun. 379:995-1000(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH ERN1.
[9]	"Deubiquitination of CXCR4 by USP14 is critical for both CXCL12-induced CXCR4 degradation and chemotaxis but not ERK activation." Mines M.A., Goodwin J.S., Limbird L.E., Cui F.F., Fan G.H. J. Biol. Chem. 284:5742-5752(2009) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CXCR4, FUNCTION, SUBCELLULAR LOCATION.
[10]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-143, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[11]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-449, MASS SPECTROMETRY.
[12]	"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis." Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M. Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-143 AND THR-235, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[13]	"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].
[14]	"System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation." Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B. Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-143, MASS SPECTROMETRY.
[15]	"Structure and mechanisms of the proteasome-associated deubiquitinating enzyme USP14." Hu M., Li P., Song L., Jeffrey P.D., Chenova T.A., Wilkinson K.D., Cohen R.E., Shi Y. EMBO J. 24:3747-3756(2005) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.2 ANGSTROMS) OF 91-494, CATALYTIC ACTIVITY, ACTIVE SITE.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U30888 mRNA. Translation: AAB60365.1.
BT007183 mRNA. Translation: AAP35847.1.
BC003556 mRNA. Translation: AAH03556.1.

IPI

IPI00219913.

PIR

G01932.

RefSeq

NP_001032411.1. NM_001037334.1.
NP_005142.1. NM_005151.3.

UniGene

Hs.464416.
Hs.707058.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2AYN	X-ray	3.20	A/B/C	91-494	[»]
2AYO	X-ray	3.50	A	91-494	[»]

ProteinModelPortal

P54578.

ModBase

Search...

Protein-protein interaction databases

IntAct

P54578. 28 interactions.

MINT

MINT-3020275.

STRING

9606.ENSP00000261601.

Protein family/group databases

MEROPS

C19.015.

PTM databases

PhosphoSite

P54578.

Polymorphism databases

DMDM

1729927.

2D gel databases

OGP

P54578.

Proteomic databases

PaxDb

P54578.

PeptideAtlas

P54578.

PRIDE

P54578.

Protocols and materials databases

DNASU

9097.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000261601; ENSP00000261601; ENSG00000101557.

GeneID

9097.

KEGG

hsa:9097.

UCSC

uc002kkf.1. human.

Organism-specific databases

CTD

9097.

GeneCards

GC18P000148.

HGNC

HGNC:12612. USP14.

HPA

HPA001308.

MIM

607274. gene.

neXtProt

NX_P54578.

PharmGKB

PA37238.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG286607.

HOGENOM

HOG000202292.

HOVERGEN

HBG054185.

InParanoid

P54578.

KO

K11843.

OMA

YGPRRIE.

PhylomeDB

P54578.

Gene expression databases

ArrayExpress

P54578.

Bgee

P54578.

CleanEx

HS_USP14.

Genevestigator

P54578.

GermOnline

ENSG00000101557. Homo sapiens.

Family and domain databases

InterPro

IPR018200. Pept_C19ubi-hydrolase_C_CS.
IPR001394. Peptidase_C19.
IPR000626. Ubiquitin.
IPR019954. Ubiquitin_CS.
IPR019955. Ubiquitin_supergroup.
[Graphical view]

Pfam

PF00443. UCH. 1 hit.
[Graphical view]

SMART

SM00213. UBQ. 1 hit.
[Graphical view]

PROSITE

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

ProtoNet

Search...

Other

ChEMBL

CHEMBL1293295.

EvolutionaryTrace

P54578.

GenomeRNAi

9097.

NextBio

34093.

SOURCE

Search...

Entry information

Entry name

UBP14_HUMAN

Accession

Primary (citable) accession number: P54578
Secondary accession number(s): Q53XY5

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	January 23, 2007
Last modified:	May 1, 2013
This is version 128 of the entry and version 3 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.