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Protein

Ubiquitin thioesterase otulin

Gene

Otulin

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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). Associates with the LUBAC complex via direct interaction with RNF31 and counteracts its action by cleaving linear polyubiquitin chains to substrates (PubMed:23708998, PubMed:27523608). 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 counteracting activity of the LUBAC complex (By similarity). Required for homeostasis of the LUBAC complex by restricting autoubiquination of the LUBAC complex subunit RNF31 (By similarity). Some results have suggested that OTULIN function is restricted to homeostasis of the LUBAC complex, because it is not stably associated with TNF or NOD2 receptor signaling complexes (RSCs) (By similarity). However, further report have shown that it plays active roles in receptor signaling (By similarity). Acts as a key negative regulator of inflammation by restricting spontaneous inflammation and maintaining immune homeostasis (PubMed:27523608). In myeloid cell, required to prevent unwarranted secretion of cytokines leading to inflammation and autoimmunity by restricting linear polyubiquitin formation (PubMed:27523608). Plays a key role in innate immune response by restricting linear polyubiquitin formation on RIPK2 in response to NOD2 stimulation, probably to limit NOD2-dependent proinflammatory signaling (By similarity).By similarity2 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

  • canonical Wnt signaling pathway Source: UniProtKB
  • innate immune response Source: UniProtKB
  • negative regulation of inflammatory response Source: UniProtKB
  • negative regulation of NF-kappaB transcription factor activity Source: UniProtKB
  • nucleotide-binding oligomerization domain containing 2 signaling pathway Source: UniProtKB
  • protein linear deubiquitination Source: UniProtKB
  • regulation of tumor necrosis factor-mediated signaling pathway Source: UniProtKB
  • sprouting angiogenesis Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Protease, Thiol protease

Keywords - Biological processi

Angiogenesis, Immunity, Innate immunity, Ubl conjugation pathway, Wnt signaling pathway

Enzyme and pathway databases

ReactomeiR-MMU-5357905. Regulation of TNFR1 signaling.

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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 15

Organism-specific databases

MGIiMGI:3577015. Otulin.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: UniProtKB
  • LUBAC complex Source: Ensembl
Complete GO annotation...

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. 1 Publication1
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.
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).By similarity

Protein-protein interaction databases

BioGridi240910. 1 interactor.
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
Contains 1 OTU domain.Curated

Keywords - Domaini

Coiled coil

Phylogenomic databases

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

Family and domain databases

InterProiIPR023235. FAM105.
IPR023237. Otulin.
[Graphical view]
PfamiPF16218. Peptidase_C101. 1 hit.
[Graphical view]
PRINTSiPR02055. PROTEINF105.
PR02057. PROTEINF105B.

Sequencei

Sequence statusi: Complete.

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

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.

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. 1 interactor.
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.
OMAiKYNTEEF.
OrthoDBiEOG091G0BXG.
PhylomeDBiQ3UCV8.
TreeFamiTF328709.

Enzyme and pathway databases

ReactomeiR-MMU-5357905. Regulation of TNFR1 signaling.

Miscellaneous databases

PROiQ3UCV8.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000046034.
GenevisibleiQ3UCV8. MM.

Family and domain databases

InterProiIPR023235. FAM105.
IPR023237. Otulin.
[Graphical view]
PfamiPF16218. Peptidase_C101. 1 hit.
[Graphical view]
PRINTSiPR02055. PROTEINF105.
PR02057. PROTEINF105B.
ProtoNetiSearch...

Entry informationi

Entry nameiOTUL_MOUSE
AccessioniPrimary (citable) accession number: Q3UCV8
Secondary accession number(s): Q3UY59, Q5M8N1, Q8R027
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 28, 2006
Last sequence update: October 11, 2005
Last modified: November 30, 2016
This is version 79 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Peptidase families
    Classification of peptidase families and list of entries
  3. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.