UniProtKB - Q3UCV8 (OTUL_MOUSE)
Protein
Ubiquitin thioesterase otulin
Gene
Otulin
Organism
Mus musculus (Mouse)
Status
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 EC:3.4.19.12
Sites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Active sitei | 126 | 1 Publication | 1 | |
Active sitei | 129 | Nucleophile1 Publication | 1 | |
Binding sitei | 314 | Linear diubiquitin | 1 | |
Active sitei | 339 | 1 Publication | 1 |
GO - Molecular functioni
- cysteine-type peptidase activity Source: UniProtKB
- thiol-dependent ubiquitin-specific protease activity Source: UniProtKB
GO - Biological processi
- 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 canonical Wnt signaling pathway Source: UniProtKB
- regulation of tumor necrosis factor-mediated signaling pathway Source: UniProtKB
- sprouting angiogenesis Source: UniProtKB
- Wnt signaling pathway Source: UniProtKB-KW
Keywordsi
Molecular function | Hydrolase, Protease, Thiol protease |
Biological process | Angiogenesis, Immunity, Innate immunity, Ubl conjugation pathway, Wnt signaling pathway |
Enzyme and pathway databases
Reactomei | R-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 | |
Organismi | Mus musculus (Mouse) |
Taxonomic identifieri | 10090 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Myomorpha › Muroidea › Muridae › Murinae › Mus › Mus |
Proteomesi |
|
Organism-specific databases
MGIi | MGI:3577015, Otulin |
Subcellular locationi
Cytoplasm and Cytosol
- Cytoplasm 1 Publication
Other locations
- cytoplasm Source: UniProtKB
Keywords - Cellular componenti
CytoplasmPathology & 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 key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Mutagenesisi | 96 | W → R in Gum(W96R) mutant; defects in embryonic angiogenesis. Embryos appear normal before 11.5 dpc but die between 12.5 dpc-14 dpc, probably due to defects in organization of branching vascular networks in the head and trunk. 1 Publication | 1 | |
Mutagenesisi | 129 | C → 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 Publications | 1 | |
Mutagenesisi | 336 | D → E in Gum(D366E) mutant; defects in embryonic angiogenesis. Weaker mutant compared to Gum(W96R) mutant. 1 Publication | 1 | |
Mutagenesisi | 349 – 352 | ETSV → AAAA: Does not affect interaction with RNF31. 1 Publication | 4 |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000261638 | 1 – 352 | Ubiquitin thioesterase otulinAdd BLAST | 352 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Modified residuei | 56 | PhosphotyrosineBy similarity | 1 |
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 conjugationProteomic databases
EPDi | Q3UCV8 |
MaxQBi | Q3UCV8 |
PaxDbi | Q3UCV8 |
PeptideAtlasi | Q3UCV8 |
PRIDEi | Q3UCV8 |
ProteomicsDBi | 294136 |
PTM databases
iPTMneti | Q3UCV8 |
PhosphoSitePlusi | Q3UCV8 |
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
Bgeei | ENSMUSG00000046034, Expressed in embryo and 252 other tissues |
ExpressionAtlasi | Q3UCV8, baseline and differential |
Genevisiblei | Q3UCV8, MM |
Interactioni
Subunit structurei
Protein-protein interaction databases
BioGRIDi | 240910, 3 interactors |
STRINGi | 10090.ENSMUSP00000057893 |
Miscellaneous databases
RNActi | Q3UCV8, protein |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 118 – 346 | OTUAdd BLAST | 229 |
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 95 – 96 | Linear diubiquitin bindingBy similarity | 2 | |
Regioni | 124 – 126 | Linear diubiquitin bindingBy similarity | 3 | |
Regioni | 255 – 259 | Linear diubiquitin bindingBy similarity | 5 | |
Regioni | 283 – 289 | Linear diubiquitin bindingBy similarity | 7 | |
Regioni | 336 – 338 | Linear diubiquitin bindingBy similarity | 3 |
Coiled coil
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Coiled coili | 49 – 73 | Sequence analysisAdd BLAST | 25 |
Motif
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Motifi | 52 – 57 | PIM motifBy similarity | 6 | |
Motifi | 349 – 352 | PDZ-binding | 4 |
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
Keywords - Domaini
Coiled coilPhylogenomic databases
eggNOGi | ENOG502QTB8, Eukaryota |
GeneTreei | ENSGT00390000009802 |
HOGENOMi | CLU_051856_1_1_1 |
InParanoidi | Q3UCV8 |
OMAi | EDWPVVT |
OrthoDBi | 1416236at2759 |
PhylomeDBi | Q3UCV8 |
TreeFami | TF328709 |
Family and domain databases
Gene3Di | 1.20.1300.20, 1 hit 3.30.200.60, 1 hit |
InterProi | View protein in InterPro IPR023235, FAM105 IPR023237, Otulin IPR042468, Peptidase_C65_otubain_sub1 IPR042467, Peptidase_C65_otubain_sub2 |
PANTHERi | PTHR33662, PTHR33662, 1 hit |
Pfami | View protein in Pfam PF16218, Peptidase_C101, 1 hit |
PRINTSi | PR02055, PROTEINF105 PR02057, PROTEINF105B |
(1+)i Sequence
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
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
Computationally mapped potential isoform sequencesi
There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basketA0A2I3BRS5 | A0A2I3BRS5_MOUSE | Ubiquitin thioesterase otulin | Otulin | 154 | Annotation score: | ||
A0A2I3BQB7 | A0A2I3BQB7_MOUSE | Ubiquitin thioesterase otulin | Otulin | 58 | Annotation score: |
Sequence cautioni
The sequence AAH87945 differs from that shown. Reason: Erroneous initiation. Truncated N-terminus.Curated
The sequence BAE22354 differs from that shown. Reason: Erroneous initiation. Truncated N-terminus.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. |
CCDSi | CCDS49586.1 |
RefSeqi | NP_001013814.2, NM_001013792.2 |
Genome annotation databases
Ensembli | ENSMUST00000059662; ENSMUSP00000057893; ENSMUSG00000046034 |
GeneIDi | 432940 |
KEGGi | mmu:432940 |
UCSCi | uc007vjr.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. |
CCDSi | CCDS49586.1 |
RefSeqi | NP_001013814.2, NM_001013792.2 |
3D structure databases
SMRi | Q3UCV8 |
ModBasei | Search... |
Protein-protein interaction databases
BioGRIDi | 240910, 3 interactors |
STRINGi | 10090.ENSMUSP00000057893 |
PTM databases
iPTMneti | Q3UCV8 |
PhosphoSitePlusi | Q3UCV8 |
Proteomic databases
EPDi | Q3UCV8 |
MaxQBi | Q3UCV8 |
PaxDbi | Q3UCV8 |
PeptideAtlasi | Q3UCV8 |
PRIDEi | Q3UCV8 |
ProteomicsDBi | 294136 |
Protocols and materials databases
Antibodypediai | 56178, 80 antibodies |
Genome annotation databases
Ensembli | ENSMUST00000059662; ENSMUSP00000057893; ENSMUSG00000046034 |
GeneIDi | 432940 |
KEGGi | mmu:432940 |
UCSCi | uc007vjr.1, mouse |
Organism-specific databases
CTDi | 90268 |
MGIi | MGI:3577015, Otulin |
Phylogenomic databases
eggNOGi | ENOG502QTB8, Eukaryota |
GeneTreei | ENSGT00390000009802 |
HOGENOMi | CLU_051856_1_1_1 |
InParanoidi | Q3UCV8 |
OMAi | EDWPVVT |
OrthoDBi | 1416236at2759 |
PhylomeDBi | Q3UCV8 |
TreeFami | TF328709 |
Enzyme and pathway databases
Reactomei | R-MMU-5357905, Regulation of TNFR1 signaling R-MMU-8866652, Synthesis of active ubiquitin: roles of E1 and E2 enzymes |
Miscellaneous databases
BioGRID-ORCSi | 432940, 9 hits in 56 CRISPR screens |
ChiTaRSi | Otulin, mouse |
PROi | PR:Q3UCV8 |
RNActi | Q3UCV8, protein |
SOURCEi | Search... |
Gene expression databases
Bgeei | ENSMUSG00000046034, Expressed in embryo and 252 other tissues |
ExpressionAtlasi | Q3UCV8, baseline and differential |
Genevisiblei | Q3UCV8, MM |
Family and domain databases
Gene3Di | 1.20.1300.20, 1 hit 3.30.200.60, 1 hit |
InterProi | View protein in InterPro IPR023235, FAM105 IPR023237, Otulin IPR042468, Peptidase_C65_otubain_sub1 IPR042467, Peptidase_C65_otubain_sub2 |
PANTHERi | PTHR33662, PTHR33662, 1 hit |
Pfami | View protein in Pfam PF16218, Peptidase_C101, 1 hit |
PRINTSi | PR02055, PROTEINF105 PR02057, PROTEINF105B |
ProtoNeti | Search... |
MobiDBi | Search... |
Entry informationi
Entry namei | OTUL_MOUSE | |
Accessioni | Q3UCV8Primary (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: | April 7, 2021 | |
This is version 104 of the entry and version 1 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program |
Miscellaneousi
Keywords - Technical termi
Reference proteomeDocuments
- Peptidase families
Classification of peptidase families and list of entries - MGD cross-references
Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot - SIMILARITY comments
Index of protein domains and families