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Protein

Ubiquitin thioesterase OTUB1

Gene

OTUB1

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

Functioni

Hydrolase that can specifically remove 'Lys-48'-linked conjugated ubiquitin from proteins and plays an important regulatory role at the level of protein turnover by preventing degradation. Regulator of T-cell anergy, a phenomenon that occurs when T-cells are rendered unresponsive to antigen rechallenge and no longer respond to their cognate antigen. Acts via its interaction with RNF128/GRAIL, a crucial inductor of CD4 T-cell anergy. Isoform 1 destabilizes RNF128, leading to prevent anergy. In contrast, isoform 2 stabilizes RNF128 and promotes anergy. Surprisingly, it regulates RNF128-mediated ubiquitination, but does not deubiquitinate polyubiquitinated RNF128. Deubiquitinates estrogen receptor alpha (ESR1). Mediates deubiquitination of 'Lys-48'-linked polyubiquitin chains, but not 'Lys-63'-linked polyubiquitin chains. Not able to cleave di-ubiquitin. Also capable of removing NEDD8 from NEDD8 conjugates, but with a much lower preference compared to 'Lys-48'-linked ubiquitin.
Plays a key non-catalytic role in DNA repair regulation by inhibiting activity of RNF168, an E3 ubiquitin-protein ligase that promotes accumulation of 'Lys-63'-linked histone H2A and H2AX at DNA damage sites. Inhibits RNF168 independently of ubiquitin thioesterase activity by binding and inhibiting UBE2N/UBC13, the E2 partner of RNF168, thereby limiting spreading of 'Lys-63'-linked histone H2A and H2AX marks. Inhibition occurs by binding to free ubiquitin: free ubiquitin acts as an allosteric regulator that increases affinity for UBE2N/UBC13 and disrupts interaction with UBE2V1. The OTUB1-UBE2N/UBC13-free ubiquitin complex adopts a configuration that mimics a cleaved 'Lys48'-linked di-ubiquitin chain.

Miscellaneous

In the structure described by PubMed:18954305, the His-265 active site of the catalytic triad is located too far to interact directly with the active site Cys-91. A possible explanation is that OTUB1 is in inactive conformation in absence of ubiquitin and a conformation change may move His-265 in the proximity of Cys-91 in presence of ubiquitin substrate.

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).1 Publication

Activity regulationi

By free ubiquitin: binding of free ubiquitin triggers conformational changes in the OTU domain and formation of a ubiquitin-binding helix in the N-terminus, promoting binding of the conjugated donor ubiquitin in UBE2N/UBC13 to OTUB1.2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei23Required for proximal ubiquitin-binding1 Publication1
Active sitei88Combined sources1 Publication1
Active sitei91Nucleophile1 Publication1 Publication1
Binding sitei221Free ubiquitin1 Publication1
Binding sitei235Free ubiquitin1 Publication1
Binding sitei237Free ubiquitin1 Publication1
Binding sitei261Free ubiquitin1 Publication1
Active sitei2651 Publication1 Publication1
Binding sitei266Free ubiquitinCombined sources2 Publications1

GO - Molecular functioni

  • NEDD8-specific protease activity Source: UniProtKB
  • thiol-dependent ubiquitin-specific protease activity Source: UniProtKB
  • ubiquitin binding Source: UniProtKB
  • ubiquitin protein ligase binding Source: UniProtKB

GO - Biological processi

Keywordsi

Molecular functionHydrolase, Protease, Thiol protease
Biological processAdaptive immunity, DNA damage, DNA repair, Immunity, Ubl conjugation pathway

Enzyme and pathway databases

ReactomeiR-HSA-5689880 Ub-specific processing proteases
R-HSA-5689896 Ovarian tumor domain proteases
SIGNORiQ96FW1

Protein family/group databases

MEROPSiC65.001

Names & Taxonomyi

Protein namesi
Recommended name:
Ubiquitin thioesterase OTUB1 (EC:3.4.19.121 Publication)
Alternative name(s):
Deubiquitinating enzyme OTUB1
OTU domain-containing ubiquitin aldehyde-binding protein 1
Otubain-1
Short name:
hOTU1
Ubiquitin-specific-processing protease OTUB1
Gene namesi
Name:OTUB1
Synonyms:OTB1, OTU1
ORF Names:HSPC263
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 11

Organism-specific databases

EuPathDBiHostDB:ENSG00000167770.11
HGNCiHGNC:23077 OTUB1
MIMi608337 gene
neXtProtiNX_Q96FW1

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

Cytoplasm

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi23C → A: Abolishes only ubiquitin-vinylsulfone adduct formation. 1 Publication1
Mutagenesisi33Q → R: Impairs inhibition of UBE2N/UBC13. 1 Publication1
Mutagenesisi37I → T: Impairs inhibition of UBE2N/UBC13. 1 Publication1
Mutagenesisi39Q → L: Does not affect activity in DNA repair and ability to inhibit UBE2N/UBC13. 1 Publication1
Mutagenesisi87P → G: Slightly improves ability to cleave 'K63'-linked ubiquitin. 1 Publication1
Mutagenesisi88D → E: Abolishes hydrolase activity in vitro. Abolishes ability to inhibit RNF168; when associated with S-91 and A-265. 2 Publications1
Mutagenesisi91C → A: Prevents RNF128 autoubiquitination, and stabilizes RNF128 in vivo. Abolishes both ubiquitin-binding and adduct formation with ubiquitin-vinylsulfone. 7 Publications1
Mutagenesisi91C → S: Abolishes hydrolase activity in vitro. Does not affect ability to inhibit RNF168. Abolishes ability to inhibit RNF168; when associated with A-88 and A-265. 7 Publications1
Mutagenesisi116A → T: Does not affect ability to inhibit UBE2N/UBC13. 1 Publication1
Mutagenesisi134T → R: Impairs inhibition of UBE2N/UBC13. 1 Publication1
Mutagenesisi137D → G: Impairs inhibition of UBE2N/UBC13. 1 Publication1
Mutagenesisi176R → L: No effect on RNF128. 1 Publication1
Mutagenesisi190F → S: Fails to inhibit ubiquitin conjugation by UBE2N/UBC13. 1 Publication1
Mutagenesisi212C → A: No effect on RNF128. 2 Publications1
Mutagenesisi261Y → H: Impairs inhibition of UBE2N/UBC13. 1 Publication1
Mutagenesisi263P → L: Fails to inhibit ubiquitin conjugation by UBE2N/UBC13. 1 Publication1
Mutagenesisi265H → A: Abolishes ability to inhibit RNF168; when associated with A-88 and S-91. 2 Publications1
Mutagenesisi265H → R: Abolishes hydrolase activity in vitro. 2 Publications1

Organism-specific databases

DisGeNETi55611
OpenTargetsiENSG00000167770
PharmGKBiPA134988141

Polymorphism and mutation databases

BioMutaiOTUB1
DMDMi44888286

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedCombined sources
ChainiPRO_00002210082 – 271Ubiquitin thioesterase OTUB1Add BLAST270

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylalanineCombined sources1
Modified residuei16PhosphoserineCombined sources1

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiQ96FW1
MaxQBiQ96FW1
PaxDbiQ96FW1
PeptideAtlasiQ96FW1
PRIDEiQ96FW1
ProteomicsDBi76566
76567 [Q96FW1-2]

PTM databases

iPTMnetiQ96FW1
PhosphoSitePlusiQ96FW1
SwissPalmiQ96FW1

Expressioni

Tissue specificityi

Isoform 1 is ubiquitous. Isoform 2 is expressed only in lymphoid tissues such as tonsils, lymph nodes and spleen, as well as peripheral blood mononuclear cells.2 Publications

Gene expression databases

BgeeiENSG00000167770 Expressed in 233 organ(s), highest expression level in anterior cingulate cortex
CleanExiHS_OTUB1
ExpressionAtlasiQ96FW1 baseline and differential
GenevisibleiQ96FW1 HS

Organism-specific databases

HPAiCAB072836
HPA039176

Interactioni

Subunit structurei

Isoform 1 and isoform 2 interact with RNF128. Isoform 1 forms a ternary complex with RNF128 and USP8. Isoform 1 interacts with the C-terminal UCH catalytic domain of USP8. Isoform 2 does not associate with USP8. Interacts with FUS, ESR1 and RACK1. Interacts with UBE2N/UBC13.6 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi120751, 213 interactors
DIPiDIP-41158N
IntActiQ96FW1, 330 interactors
MINTiQ96FW1
STRINGi9606.ENSP00000402551

Structurei

Secondary structure

1271
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ96FW1
SMRiQ96FW1
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ96FW1

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini80 – 271OTUPROSITE-ProRule annotationAdd BLAST192

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni130 – 138Ubiquitin-conjugating enzyme E2 binding1 Publication9
Regioni169 – 177Ubiquitin-conjugating enzyme E2 binding1 Publication9
Regioni189 – 195Free ubiquitin bindingCombined sources2 Publications7
Regioni206 – 213Ubiquitin-conjugating enzyme E2 bindingCombined sources2 Publications8
Regioni214 – 221Free ubiquitin bindingCombined sources2 Publications8
Regioni245 – 251Free ubiquitin bindingCombined sources2 Publications7

Domaini

In addition to ubiquitin-binding at the Cys-91 active site, a proximal ubiquitin-binding site is also present at Cys-23 Occupancy of the active site is needed to enable tight binding to the second site. Distinct binding sites for the ubiquitins may allow to discriminate among different isopeptide linkages (i.e. 'Lys-48'-, 'Lys-63'-linked polyubiquitin) in polyubiquitin substrates and achieve linkage-specific deubiquitination.1 Publication

Sequence similaritiesi

Belongs to the peptidase C65 family.Curated

Phylogenomic databases

eggNOGiKOG3991 Eukaryota
ENOG410ZMN7 LUCA
GeneTreeiENSGT00390000006979
HOVERGENiHBG053383
InParanoidiQ96FW1
KOiK09602
PhylomeDBiQ96FW1
TreeFamiTF314145

Family and domain databases

InterProiView protein in InterPro
IPR003323 OTU_dom
IPR030298 OTUB1
IPR016615 Otubain
IPR038765 Papain_like_cys_pep_sf
IPR019400 Peptidase_C65_otubain
PANTHERiPTHR12931 PTHR12931, 1 hit
PTHR12931:SF19 PTHR12931:SF19, 1 hit
PfamiView protein in Pfam
PF10275 Peptidase_C65, 1 hit
PIRSFiPIRSF013503 Ubiquitin_thioesterase_Otubain, 1 hit
SUPFAMiSSF54001 SSF54001, 1 hit
PROSITEiView protein in PROSITE
PS50802 OTU, 1 hit

Sequences (2+)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 2 described isoforms and 6 potential isoforms that are computationally mapped.iShow all

Isoform 1 (identifier: Q96FW1-1) [UniParc]FASTAAdd to basket
Also known as: Otubain-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.

« Hide
        10         20         30         40         50
MAAEEPQQQK QEPLGSDSEG VNCLAYDEAI MAQQDRIQQE IAVQNPLVSE
60 70 80 90 100
RLELSVLYKE YAEDDNIYQQ KIKDLHKKYS YIRKTRPDGN CFYRAFGFSH
110 120 130 140 150
LEALLDDSKE LQRFKAVSAK SKEDLVSQGF TEFTIEDFHN TFMDLIEQVE
160 170 180 190 200
KQTSVADLLA SFNDQSTSDY LVVYLRLLTS GYLQRESKFF EHFIEGGRTV
210 220 230 240 250
KEFCQQEVEP MCKESDHIHI IALAQALSVS IQVEYMDRGE GGTTNPHIFP
260 270
EGSEPKVYLL YRPGHYDILY K
Length:271
Mass (Da):31,284
Last modified:March 1, 2004 - v2
Checksum:i63188EE1DC5FD66F
GO
Isoform 2 (identifier: Q96FW1-2) [UniParc]FASTAAdd to basket
Also known as: ARF-1

The sequence of this isoform differs from the canonical sequence as follows:
     1-112: MAAEEPQQQK...ALLDDSKELQ → MMKPSWLSRT...MLGPPFHPTP

Note: Lacks the catalytic sites for protease activity.
Show »
Length:315
Mass (Da):35,285
Checksum:i3B37EB8F1B3B2404
GO

Computationally mapped potential isoform sequencesi

There are 6 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
J3KR44J3KR44_HUMAN
Ubiquitin thioesterase
OTUB1
272Annotation score:
F5H6Q1F5H6Q1_HUMAN
Ubiquitin thioesterase
OTUB1
280Annotation score:
F5GYN4F5GYN4_HUMAN
Ubiquitin thioesterase OTUB1
OTUB1
241Annotation score:
F5GYJ8F5GYJ8_HUMAN
Ubiquitin thioesterase OTUB1
OTUB1
286Annotation score:
F5H3F0F5H3F0_HUMAN
Ubiquitin thioesterase OTUB1
OTUB1
170Annotation score:
F5H4F3F5H4F3_HUMAN
Ubiquitin thioesterase OTUB1
OTUB1
102Annotation score:

Sequence cautioni

The sequence AAF28941 differs from that shown. Reason: Erroneous initiation.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti61Y → C in AAH10368 (PubMed:15489334).Curated1
Sequence conflicti151K → R in BAA90956 (PubMed:14702039).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0094641 – 112MAAEE…SKELQ → MMKPSWLSRTEFSKRLLCRT LWCQSGWSSRSYTRSMLKMT TSINRRSRTSTKSTRTSARP GLTATVSIGLSDSPTWRHCW MTARSCSGEKGGHWAPRQVG VYLLPGRVGCVSSRVSPSFP GDGLDSGLARRGSAVSALAS GLVEEPMLGPPFHPTP in isoform 2. 1 PublicationAdd BLAST112

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY177200 mRNA Translation: AAO27702.1
AF161381 mRNA Translation: AAF28941.1 Different initiation.
AK000120 mRNA Translation: BAA90956.1
AP000721 Genomic DNA No translation available.
BC007519 mRNA Translation: AAH07519.1
BC010368 mRNA Translation: AAH10368.1
BC107701 mRNA Translation: AAI07702.1
CCDSiCCDS8055.1 [Q96FW1-1]
RefSeqiNP_060140.2, NM_017670.2 [Q96FW1-1]
UniGeneiHs.473788

Genome annotation databases

EnsembliENST00000428192; ENSP00000402551; ENSG00000167770 [Q96FW1-1]
ENST00000538426; ENSP00000444357; ENSG00000167770 [Q96FW1-1]
GeneIDi55611
KEGGihsa:55611
UCSCiuc001nyf.2 human [Q96FW1-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY177200 mRNA Translation: AAO27702.1
AF161381 mRNA Translation: AAF28941.1 Different initiation.
AK000120 mRNA Translation: BAA90956.1
AP000721 Genomic DNA No translation available.
BC007519 mRNA Translation: AAH07519.1
BC010368 mRNA Translation: AAH10368.1
BC107701 mRNA Translation: AAI07702.1
CCDSiCCDS8055.1 [Q96FW1-1]
RefSeqiNP_060140.2, NM_017670.2 [Q96FW1-1]
UniGeneiHs.473788

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2ZFYX-ray1.69A40-271[»]
3VONX-ray3.15A/H/O/V/c/j45-271[»]
4DDGX-ray3.30A/B/C/J/K/L25-271[»]
4DDIX-ray3.80A/B/C25-271[»]
4DHZX-ray3.11A1-45[»]
4I6LX-ray2.49A45-271[»]
4LDTX-ray1.90A1-45[»]
ProteinModelPortaliQ96FW1
SMRiQ96FW1
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi120751, 213 interactors
DIPiDIP-41158N
IntActiQ96FW1, 330 interactors
MINTiQ96FW1
STRINGi9606.ENSP00000402551

Protein family/group databases

MEROPSiC65.001

PTM databases

iPTMnetiQ96FW1
PhosphoSitePlusiQ96FW1
SwissPalmiQ96FW1

Polymorphism and mutation databases

BioMutaiOTUB1
DMDMi44888286

Proteomic databases

EPDiQ96FW1
MaxQBiQ96FW1
PaxDbiQ96FW1
PeptideAtlasiQ96FW1
PRIDEiQ96FW1
ProteomicsDBi76566
76567 [Q96FW1-2]

Protocols and materials databases

DNASUi55611
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000428192; ENSP00000402551; ENSG00000167770 [Q96FW1-1]
ENST00000538426; ENSP00000444357; ENSG00000167770 [Q96FW1-1]
GeneIDi55611
KEGGihsa:55611
UCSCiuc001nyf.2 human [Q96FW1-1]

Organism-specific databases

CTDi55611
DisGeNETi55611
EuPathDBiHostDB:ENSG00000167770.11
GeneCardsiOTUB1
HGNCiHGNC:23077 OTUB1
HPAiCAB072836
HPA039176
MIMi608337 gene
neXtProtiNX_Q96FW1
OpenTargetsiENSG00000167770
PharmGKBiPA134988141
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG3991 Eukaryota
ENOG410ZMN7 LUCA
GeneTreeiENSGT00390000006979
HOVERGENiHBG053383
InParanoidiQ96FW1
KOiK09602
PhylomeDBiQ96FW1
TreeFamiTF314145

Enzyme and pathway databases

ReactomeiR-HSA-5689880 Ub-specific processing proteases
R-HSA-5689896 Ovarian tumor domain proteases
SIGNORiQ96FW1

Miscellaneous databases

ChiTaRSiOTUB1 human
EvolutionaryTraceiQ96FW1
GeneWikiiOTUB1
GenomeRNAii55611
PROiPR:Q96FW1
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000167770 Expressed in 233 organ(s), highest expression level in anterior cingulate cortex
CleanExiHS_OTUB1
ExpressionAtlasiQ96FW1 baseline and differential
GenevisibleiQ96FW1 HS

Family and domain databases

InterProiView protein in InterPro
IPR003323 OTU_dom
IPR030298 OTUB1
IPR016615 Otubain
IPR038765 Papain_like_cys_pep_sf
IPR019400 Peptidase_C65_otubain
PANTHERiPTHR12931 PTHR12931, 1 hit
PTHR12931:SF19 PTHR12931:SF19, 1 hit
PfamiView protein in Pfam
PF10275 Peptidase_C65, 1 hit
PIRSFiPIRSF013503 Ubiquitin_thioesterase_Otubain, 1 hit
SUPFAMiSSF54001 SSF54001, 1 hit
PROSITEiView protein in PROSITE
PS50802 OTU, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiOTUB1_HUMAN
AccessioniPrimary (citable) accession number: Q96FW1
Secondary accession number(s): Q32Q78
, Q96II3, Q9NXQ4, Q9P0B8
Entry historyiIntegrated into UniProtKB/Swiss-Prot: March 1, 2004
Last sequence update: March 1, 2004
Last modified: September 12, 2018
This is version 162 of the entry and version 2 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, Direct protein sequencing, Reference proteome
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Main funding by: National Institutes of Health

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