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Protein

Ubiquitin thioesterase otulin

Gene

Otulin

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Deubiquitinase that specifically removes linear ('Met-1'-linked) polyubiquitin chains to substrates and acts as a regulator of angiogenesis and innate immune response (PubMed:23708998, PubMed:27523608, PubMed:29950720). Required during angiogenesis, craniofacial and neuronal development by regulating the canonical Wnt signaling together with the LUBAC complex (PubMed:23708998). Acts as a negative regulator of NF-kappa-B by regulating the activity of the LUBAC complex (By similarity). OTULIN function is mainly restricted to homeostasis of the LUBAC complex: acts by removing 'Met-1'-linked autoubiquitination of the LUBAC complex, thereby preventing inactivation of the LUBAC complex (PubMed:29950720). Acts as a key negative regulator of inflammation by restricting spontaneous inflammation and maintaining immune homeostasis (PubMed:27523608, PubMed:29950720). In myeloid cell, required to prevent unwarranted secretion of cytokines leading to inflammation and autoimmunity by restricting linear polyubiquitin formation (PubMed:27523608). Plays a role in innate immune response by restricting linear polyubiquitin formation on LUBAC complex in response to NOD2 stimulation, probably to limit NOD2-dependent proinflammatory signaling (By similarity).By similarity3 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).2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei1261 Publication1
Active sitei129Nucleophile1 Publication1
Binding sitei314Linear diubiquitin1
Active sitei3391 Publication1

GO - Molecular functioni

  • cysteine-type peptidase activity Source: UniProtKB
  • thiol-dependent ubiquitin-specific protease activity Source: UniProtKB

GO - Biological processi

Keywordsi

Molecular functionHydrolase, Protease, Thiol protease
Biological processAngiogenesis, Immunity, Innate immunity, Ubl conjugation pathway, Wnt signaling pathway

Enzyme and pathway databases

ReactomeiR-MMU-5357905 Regulation of TNFR1 signaling
R-MMU-8866652 Synthesis of active ubiquitin: roles of E1 and E2 enzymes

Names & Taxonomyi

Protein namesi
Recommended name:
Ubiquitin thioesterase otulinCurated (EC:3.4.19.122 Publications)
Alternative name(s):
Deubiquitinating enzyme otulinBy similarity
OTU domain-containing deubiquitinase with linear linkage specificityBy similarity
Ubiquitin thioesterase Gumby1 Publication
Gene namesi
Name:OtulinImported
Synonyms:Fam105bImported, Gum1 Publication
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 15

Organism-specific databases

MGIiMGI:3577015 Otulin

Subcellular locationi

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Disruption phenotypei

Embryonic lethality (PubMed:23708998, PubMed:27523608). Specific deletion in immune cells leads to acute systemic inflammation characterized by rapid weight loss, increased levels of pro-inflammatory cytokines in serum, neutrophilia with all the hallmarks of emergency granulopoiesis (PubMed:27523608). Specific deletion in T- or B-cells generates healthy mice with no overt inflammatory phenotypes (PubMed:27523608). In contrast, specific deletion in myeloid cells results in a strong inflammatory phenotype, characterized by chronic inflammation and autoimmunity, caused by sterile autoactivation of inflammatory pathways (PubMed:27523608).2 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi96W → R in Gum(W96R) mutant; defects in embryonic angiogenesis. Embryos appear normal before E11.5 but die between E12.5-E14, probably due to defects in organization of branching vascular networks in the head and trunk. 1 Publication1
Mutagenesisi129C → A or S: Abolishes deubiquitinase activity without affecting interaction with RNF31. Lethality at midgestation in knockin mice caused by inactivation of the LUBAC complex, leading to cell death mediated by TNFR1 and RIPK1. 2 Publications1
Mutagenesisi336D → E in Gum(D366E) mutant; defects in embryonic angiogenesis. Weaker mutant compared to Gum(W96R) mutant. 1 Publication1
Mutagenesisi349 – 352ETSV → AAAA: Does not affect interaction with RNF31. 1 Publication4

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002616381 – 352Ubiquitin thioesterase otulinAdd BLAST352

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei56PhosphotyrosineBy similarity1

Post-translational modificationi

Ubiquitinated.By similarity
Acetylated.By similarity
Phosphorylated. Phosphorylation at Tyr-56 prevents interaction with RNF31; dephosphorylation promotes interaction with RNF31 and the LUBAC complex.By similarity

Keywords - PTMi

Acetylation, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ3UCV8
MaxQBiQ3UCV8
PaxDbiQ3UCV8
PeptideAtlasiQ3UCV8
PRIDEiQ3UCV8

PTM databases

iPTMnetiQ3UCV8
PhosphoSitePlusiQ3UCV8

Expressioni

Developmental stagei

Enriched in a subset of endothelial cells near presumptive tips of vessels and vascular buds (at protein level).1 Publication

Gene expression databases

BgeeiENSMUSG00000046034 Expressed in 234 organ(s), highest expression level in embryo
GenevisibleiQ3UCV8 MM

Interactioni

Subunit structurei

Interacts (via the PUB domain) with RNF31 (via the PIM motif); the interaction is direct (PubMed:23708998). Interacts with DVL2 (PubMed:23708998).1 Publication

Protein-protein interaction databases

BioGridi240910, 3 interactors
STRINGi10090.ENSMUSP00000057893

Structurei

3D structure databases

ProteinModelPortaliQ3UCV8
SMRiQ3UCV8
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini118 – 346OTUAdd BLAST229

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni95 – 96Linear diubiquitin bindingBy similarity2
Regioni124 – 126Linear diubiquitin bindingBy similarity3
Regioni255 – 259Linear diubiquitin bindingBy similarity5
Regioni283 – 289Linear diubiquitin bindingBy similarity7
Regioni336 – 338Linear diubiquitin bindingBy similarity3

Coiled coil

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Coiled coili49 – 73Sequence analysisAdd BLAST25

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi52 – 57PIM motifBy similarity6
Motifi349 – 352PDZ-binding4

Domaini

The specificity for linear polyubiquitin is given by the 'Glu-16' residue in ubiquitin chain.By similarity
The PIM (PUB-interaction motif) motif mediates interaction with the PUB domain of RNF31. Does not interact with other PUB domain-containing proteins. Phosphorylation at Tyr-56 prevents interaction with RNF31.By similarity

Sequence similaritiesi

Belongs to the peptidase C65 family. Otulin subfamily.Curated

Keywords - Domaini

Coiled coil

Phylogenomic databases

eggNOGiENOG410IE61 Eukaryota
ENOG4111KB3 LUCA
GeneTreeiENSGT00390000009802
HOGENOMiHOG000294085
HOVERGENiHBG104927
InParanoidiQ3UCV8
KOiK18343
OMAiPRDWPVV
OrthoDBiEOG091G0BXG
PhylomeDBiQ3UCV8
TreeFamiTF328709

Family and domain databases

InterProiView protein in InterPro
IPR023235 FAM105
IPR023237 Otulin
PANTHERiPTHR33662 PTHR33662, 1 hit
PfamiView protein in Pfam
PF16218 Peptidase_C101, 1 hit
PRINTSiPR02055 PROTEINF105
PR02057 PROTEINF105B

Sequence (1+)i

Sequence statusi: Complete.

This entry has 1 described isoform and 2 potential isoforms that are computationally mapped.Show allAlign All

Q3UCV8-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MSRGTMPQPG AWPGASCAET PAREAGAAAR DGGKVTAGAQ PRAATRCPAE
60 70 80 90 100
HEEDMYRAAD EIEKEKELLI HERGISEPRL SVAPEMDIMD YCKKEWRGNT
110 120 130 140 150
QKATCMKKGY EEVSQKFTSI RRVRGDNYCA LRATLFQAMS QLAELPPWLQ
160 170 180 190 200
DLELILLPEK LINKYTWIKQ WKLGLKFDGK SEDLVEKIKE SLALLRKKWV
210 220 230 240 250
SLAAMKTAEA RQTACDELFT NEEEEYSLYE AVKFLMLNRA IELYDDKEKG
260 270 280 290 300
KEVPFFSVLL FARDTSNDPE QLLRNHLNQV GHTGGLEQVE MFLLAYAVRH
310 320 330 340 350
SIRVYRLSKY NTEEFITVYP TDPPKDWPMV TLIAEDDRHY NIPVRVCEET

SV
Length:352
Mass (Da):40,320
Last modified:October 11, 2005 - v1
Checksum:i435B9B3F4BDEEDDA
GO

Computationally mapped potential isoform sequencesi

There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
A0A2I3BQB7A0A2I3BQB7_MOUSE
Ubiquitin thioesterase otulin
Otulin
58Annotation score:
A0A2I3BRS5A0A2I3BRS5_MOUSE
Ubiquitin thioesterase otulin
Otulin
154Annotation score:

Sequence cautioni

The sequence AAH87945 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence BAE22354 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK134955 mRNA Translation: BAE22354.1 Different initiation.
AK150371 mRNA Translation: BAE29504.1
GL456173 Genomic DNA No translation available.
BC028541 mRNA Translation: AAH28541.1
BC087945 mRNA Translation: AAH87945.1 Different initiation.
CCDSiCCDS49586.1
RefSeqiNP_001013814.2, NM_001013792.2
UniGeneiMm.309164

Genome annotation databases

EnsembliENSMUST00000059662; ENSMUSP00000057893; ENSMUSG00000046034
GeneIDi432940
KEGGimmu:432940
UCSCiuc007vjr.1 mouse

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK134955 mRNA Translation: BAE22354.1 Different initiation.
AK150371 mRNA Translation: BAE29504.1
GL456173 Genomic DNA No translation available.
BC028541 mRNA Translation: AAH28541.1
BC087945 mRNA Translation: AAH87945.1 Different initiation.
CCDSiCCDS49586.1
RefSeqiNP_001013814.2, NM_001013792.2
UniGeneiMm.309164

3D structure databases

ProteinModelPortaliQ3UCV8
SMRiQ3UCV8
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi240910, 3 interactors
STRINGi10090.ENSMUSP00000057893

PTM databases

iPTMnetiQ3UCV8
PhosphoSitePlusiQ3UCV8

Proteomic databases

EPDiQ3UCV8
MaxQBiQ3UCV8
PaxDbiQ3UCV8
PeptideAtlasiQ3UCV8
PRIDEiQ3UCV8

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000059662; ENSMUSP00000057893; ENSMUSG00000046034
GeneIDi432940
KEGGimmu:432940
UCSCiuc007vjr.1 mouse

Organism-specific databases

CTDi90268
MGIiMGI:3577015 Otulin

Phylogenomic databases

eggNOGiENOG410IE61 Eukaryota
ENOG4111KB3 LUCA
GeneTreeiENSGT00390000009802
HOGENOMiHOG000294085
HOVERGENiHBG104927
InParanoidiQ3UCV8
KOiK18343
OMAiPRDWPVV
OrthoDBiEOG091G0BXG
PhylomeDBiQ3UCV8
TreeFamiTF328709

Enzyme and pathway databases

ReactomeiR-MMU-5357905 Regulation of TNFR1 signaling
R-MMU-8866652 Synthesis of active ubiquitin: roles of E1 and E2 enzymes

Miscellaneous databases

ChiTaRSiOtulin mouse
PROiPR:Q3UCV8
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000046034 Expressed in 234 organ(s), highest expression level in embryo
GenevisibleiQ3UCV8 MM

Family and domain databases

InterProiView protein in InterPro
IPR023235 FAM105
IPR023237 Otulin
PANTHERiPTHR33662 PTHR33662, 1 hit
PfamiView protein in Pfam
PF16218 Peptidase_C101, 1 hit
PRINTSiPR02055 PROTEINF105
PR02057 PROTEINF105B
ProtoNetiSearch...

Entry informationi

Entry nameiOTUL_MOUSE
AccessioniPrimary (citable) accession number: Q3UCV8
Secondary accession number(s): Q3UY59, Q5M8N1, Q8R027
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 28, 2006
Last sequence update: October 11, 2005
Last modified: November 7, 2018
This is version 90 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. Peptidase families
    Classification of peptidase families and list of entries
  3. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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