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Protein

Ubiquitin thioesterase otulin

Gene

OTULIN

Organism
Homo sapiens (Human)
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:23746843, PubMed:23806334, PubMed:23827681, PubMed:27523608, PubMed:27559085, PubMed:24726323, PubMed:24726327). Associates with the LUBAC complex via direct interaction with RNF31 and counteracts its action by cleaving linear polyubiquitin chains to substrates (PubMed:23708998, PubMed:23746843, PubMed:23806334, PubMed:23827681, PubMed:24726323, PubMed:24726327). 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 (PubMed:23746843, PubMed:23806334). Required for homeostasis of the LUBAC complex by restricting autoubiquination of the LUBAC complex subunit RNF31 (PubMed:24726323). 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) (PubMed:26670046). However, further report have shown that it plays active roles in receptor signaling (PubMed:26997266, PubMed:27523608). 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 (PubMed:23806334).9 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).3 Publications

Kineticsi

Kcat is 6.3 sec(-1) with linear diubiquitin as substrate.1 Publication

Manual assertion based on experiment ini

  1. KM=7.98 µM for linear diubiquitin1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Active sitei126Combined sources2 Publications1
    Active sitei129NucleophileCombined sources3 Publications1
    Binding sitei314Linear diubiquitinCombined sources2 Publications1
    Active sitei339Combined sources2 Publications1

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

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Ubiquitin thioesterase otulinCurated (EC:3.4.19.123 Publications)
    Alternative name(s):
    Deubiquitinating enzyme otulin1 Publication
    OTU domain-containing deubiquitinase with linear linkage specificity1 Publication
    Ubiquitin thioesterase GumbyBy similarity
    Gene namesi
    Name:OTULIN1 PublicationImported
    Synonyms:FAM105BImported
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 5

    Organism-specific databases

    HGNCiHGNC:25118. OTULIN.

    Subcellular locationi

    GO - Cellular componenti

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

    Keywords - Cellular componenti

    Cytoplasm

    Pathology & Biotechi

    Involvement in diseasei

    Autoinflammation, panniculitis, and dermatosis syndrome (AIPDS)2 Publications
    The disease is caused by mutations affecting the gene represented in this entry.
    Disease descriptionAn autosomal recessive autoinflammatory disorder characterized by neonatal-onset of fever, neutrophilic dermatitis, panniculitis, painful joints, failure to thrive. Patients do not exhibit overt primary immunodeficiency.
    See also OMIM:617099

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi54D → A: Reduced interaction with RNF31. 1 Publication1
    Mutagenesisi55M → D: Abolished interaction with RNF31. 1 Publication1
    Mutagenesisi56Y → A or D: Abolished interaction with RNF31. 2 Publications1
    Mutagenesisi56Y → E, F or W: Strongly reduced interaction with RNF31. 2 Publications1
    Mutagenesisi91Y → F: Results in strong reduction of kcat while not affecting KM. 1 Publication1
    Mutagenesisi96W → A: Decreased activity toward linear ubiquitin. 2 Publications1
    Mutagenesisi100 – 102TQK → AAA: Decreased activity toward linear ubiquitin. 1 Publication3
    Mutagenesisi129C → A or S: Abolishes deubiquitinase activity. 4 Publications1
    Mutagenesisi259L → E: Decreased affinity for linear diubiquitin. 1 Publication1
    Mutagenesisi314E → R: Decreased affinity for linear diubiquitin. 1 Publication1
    Mutagenesisi336D → A: Stabilizes H-339 in the active conformation, generating a more reactive enzyme. 1 Publication1
    Mutagenesisi339H → A: Impaired deubiquitinase activity. 1 Publication1
    Mutagenesisi341N → A: Abolishes deubiquitinase activity. 1 Publication1
    Mutagenesisi341N → D: Stabilizes H-339 in the active conformation, generating a more reactive enzyme. 1 Publication1

    Keywords - Diseasei

    Disease mutation

    Organism-specific databases

    DisGeNETi90268.
    MIMi617099. phenotype.
    OpenTargetsiENSG00000154124.
    PharmGKBiPA142671789.

    Polymorphism and mutation databases

    BioMutaiFAM105B.
    DMDMi118572305.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00002616371 – 352Ubiquitin thioesterase otulinAdd BLAST352

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei56Phosphotyrosine2 Publications1

    Post-translational modificationi

    Ubiquitinated.1 Publication
    Acetylated.1 Publication
    Phosphorylated (PubMed:23746843, PubMed:24726323, PubMed:24726327). Phosphorylation at Tyr-56 prevents interaction with RNF31; dephosphorylation promotes interaction with RNF31 and the LUBAC complex (PubMed:24726323, PubMed:24726327).3 Publications

    Keywords - PTMi

    Acetylation, Phosphoprotein, Ubl conjugation

    Proteomic databases

    EPDiQ96BN8.
    MaxQBiQ96BN8.
    PaxDbiQ96BN8.
    PeptideAtlasiQ96BN8.
    PRIDEiQ96BN8.

    PTM databases

    iPTMnetiQ96BN8.
    PhosphoSitePlusiQ96BN8.

    Expressioni

    Gene expression databases

    BgeeiENSG00000154124.
    CleanExiHS_FAM105B.
    ExpressionAtlasiQ96BN8. baseline and differential.
    GenevisibleiQ96BN8. HS.

    Organism-specific databases

    HPAiHPA051074.

    Interactioni

    Subunit structurei

    Interacts (via the PUB domain) with RNF31 (via the PIM motif); the interaction is direct (PubMed:27523608, PubMed:23708998, PubMed:23746843, PubMed:24726323, PubMed:24726327). Interacts with DVL2 (By similarity).By similarity5 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    DAZAP2Q150383EBI-750730,EBI-724310
    FAM168AQ925673EBI-750730,EBI-7957930

    Protein-protein interaction databases

    BioGridi124684. 22 interactors.
    IntActiQ96BN8. 5 interactors.
    MINTiMINT-7944191.
    STRINGi9606.ENSP00000284274.

    Structurei

    Secondary structure

    1352
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Beta strandi55 – 57Combined sources3
    Helixi59 – 63Combined sources5
    Helixi88 – 95Combined sources8
    Helixi101 – 114Combined sources14
    Beta strandi118 – 121Combined sources4
    Helixi129 – 140Combined sources12
    Helixi147 – 150Combined sources4
    Helixi153 – 164Combined sources12
    Helixi166 – 170Combined sources5
    Helixi184 – 204Combined sources21
    Helixi208 – 218Combined sources11
    Beta strandi220 – 222Combined sources3
    Helixi223 – 248Combined sources26
    Helixi255 – 262Combined sources8
    Beta strandi263 – 265Combined sources3
    Helixi269 – 275Combined sources7
    Helixi277 – 279Combined sources3
    Turni280 – 282Combined sources3
    Helixi288 – 298Combined sources11
    Beta strandi301 – 306Combined sources6
    Helixi307 – 309Combined sources3
    Helixi313 – 315Combined sources3
    Beta strandi316 – 322Combined sources7
    Beta strandi329 – 336Combined sources8
    Beta strandi339 – 344Combined sources6
    Helixi346 – 348Combined sources3

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    3ZNVX-ray1.30A80-352[»]
    3ZNXX-ray1.35A80-352[»]
    3ZNZX-ray1.90A80-352[»]
    4KSJX-ray1.60A79-352[»]
    4KSKX-ray2.40A/B55-352[»]
    4KSLX-ray2.83A/B/E/G/I/K/M/O/Q/S/U/W79-352[»]
    4OYKX-ray2.00C/D49-67[»]
    4P0BX-ray2.70B/D52-61[»]
    ProteinModelPortaliQ96BN8.
    SMRiQ96BN8.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini118 – 346OTUPROSITE-ProRule annotationAdd BLAST229

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni95 – 96Linear diubiquitin bindingCombined sources2 Publications2
    Regioni124 – 126Linear diubiquitin bindingCombined sources2 Publications3
    Regioni255 – 259Linear diubiquitin bindingCombined sources2 Publications5
    Regioni283 – 289Linear diubiquitin bindingCombined sources2 Publications7
    Regioni336 – 338Linear diubiquitin bindingCombined sources2 Publications3

    Motif

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Motifi52 – 57PIM motif2 Publications6

    Domaini

    The specificity for linear polyubiquitin is given by the 'Glu-16' residue in ubiquitin chain.1 Publication
    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 RNF31.2 Publications

    Sequence similaritiesi

    Belongs to the peptidase C65 family. Otulin subfamily.Curated
    Contains 1 OTU domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiENOG410IE61. Eukaryota.
    ENOG4111KB3. LUCA.
    GeneTreeiENSGT00390000009802.
    HOGENOMiHOG000294085.
    HOVERGENiHBG104927.
    InParanoidiQ96BN8.
    KOiK18343.
    OMAiKYNTEEF.
    OrthoDBiEOG091G0BXG.
    PhylomeDBiQ96BN8.
    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.

    Q96BN8-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MSRGTMPQPE AWPGASCAET PAREAAATAR DGGKAAASGQ PRPEMQCPAE
    60 70 80 90 100
    HEEDMYRAAD EIEKEKELLI HERGASEPRL SVAPEMDIMD YCKKEWRGNT
    110 120 130 140 150
    QKATCMKMGY EEVSQKFTSI RRVRGDNYCA LRATLFQAMS QAVGLPPWLQ
    160 170 180 190 200
    DPELMLLPEK LISKYNWIKQ WKLGLKFDGK NEDLVDKIKE SLTLLRKKWA
    210 220 230 240 250
    GLAEMRTAEA RQIACDELFT NEAEEYSLYE AVKFLMLNRA IELYNDKEKG
    260 270 280 290 300
    KEVPFFSVLL FARDTSNDPG QLLRNHLNQV GHTGGLEQVE MFLLAYAVRH
    310 320 330 340 350
    TIQVYRLSKY NTEEFITVYP TDPPKDWPVV TLIAEDDRHY NIPVRVCEET

    SL
    Length:352
    Mass (Da):40,263
    Last modified:November 28, 2006 - v3
    Checksum:i65071FF7B427C2FA
    GO

    Sequence cautioni

    The sequence AAH07706 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
    The sequence AAH15392 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
    The sequence BAC03828 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti211R → G in BAC03828 (PubMed:14702039).Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_053819155M → L.Corresponds to variant rs11953822dbSNPEnsembl.1
    Natural variantiVAR_029469227S → N.Corresponds to variant rs9312870dbSNPEnsembl.1
    Natural variantiVAR_076865244Y → C in ORAS; slightly impaired ability to mediate deubiquitination of linear polyubiquitin chains; does not affect ability to interact with RNF31. 1 Publication1
    Natural variantiVAR_076866272L → P in ORAS; decreased stability; impaired ability to mediate deubiquitination of linear polyubiquitin chains; increased NF-kappa-B signaling; does not affect ability to interact with RNF31. 2 Publications1
    Natural variantiVAR_053820311N → S.Corresponds to variant rs9312870dbSNPEnsembl.1

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AC010491 Genomic DNA. No translation available.
    CH471102 Genomic DNA. Translation: EAX08038.1.
    CH471102 Genomic DNA. Translation: EAX08039.1.
    BC007706 mRNA. Translation: AAH07706.3. Different initiation.
    BC015392 mRNA. Translation: AAH15392.2. Different initiation.
    AK092203 mRNA. Translation: BAC03828.1. Different initiation.
    CCDSiCCDS43302.1.
    RefSeqiNP_612357.4. NM_138348.5.
    XP_011512453.1. XM_011514151.2.
    XP_011512454.1. XM_011514152.2.
    UniGeneiHs.406335.

    Genome annotation databases

    EnsembliENST00000284274; ENSP00000284274; ENSG00000154124.
    GeneIDi90268.
    KEGGihsa:90268.
    UCSCiuc003jfk.4. human.

    Keywords - Coding sequence diversityi

    Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AC010491 Genomic DNA. No translation available.
    CH471102 Genomic DNA. Translation: EAX08038.1.
    CH471102 Genomic DNA. Translation: EAX08039.1.
    BC007706 mRNA. Translation: AAH07706.3. Different initiation.
    BC015392 mRNA. Translation: AAH15392.2. Different initiation.
    AK092203 mRNA. Translation: BAC03828.1. Different initiation.
    CCDSiCCDS43302.1.
    RefSeqiNP_612357.4. NM_138348.5.
    XP_011512453.1. XM_011514151.2.
    XP_011512454.1. XM_011514152.2.
    UniGeneiHs.406335.

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    3ZNVX-ray1.30A80-352[»]
    3ZNXX-ray1.35A80-352[»]
    3ZNZX-ray1.90A80-352[»]
    4KSJX-ray1.60A79-352[»]
    4KSKX-ray2.40A/B55-352[»]
    4KSLX-ray2.83A/B/E/G/I/K/M/O/Q/S/U/W79-352[»]
    4OYKX-ray2.00C/D49-67[»]
    4P0BX-ray2.70B/D52-61[»]
    ProteinModelPortaliQ96BN8.
    SMRiQ96BN8.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi124684. 22 interactors.
    IntActiQ96BN8. 5 interactors.
    MINTiMINT-7944191.
    STRINGi9606.ENSP00000284274.

    PTM databases

    iPTMnetiQ96BN8.
    PhosphoSitePlusiQ96BN8.

    Polymorphism and mutation databases

    BioMutaiFAM105B.
    DMDMi118572305.

    Proteomic databases

    EPDiQ96BN8.
    MaxQBiQ96BN8.
    PaxDbiQ96BN8.
    PeptideAtlasiQ96BN8.
    PRIDEiQ96BN8.

    Protocols and materials databases

    DNASUi90268.
    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000284274; ENSP00000284274; ENSG00000154124.
    GeneIDi90268.
    KEGGihsa:90268.
    UCSCiuc003jfk.4. human.

    Organism-specific databases

    CTDi90268.
    DisGeNETi90268.
    GeneCardsiOTULIN.
    HGNCiHGNC:25118. OTULIN.
    HPAiHPA051074.
    MIMi615712. gene.
    617099. phenotype.
    neXtProtiNX_Q96BN8.
    OpenTargetsiENSG00000154124.
    PharmGKBiPA142671789.
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiENOG410IE61. Eukaryota.
    ENOG4111KB3. LUCA.
    GeneTreeiENSGT00390000009802.
    HOGENOMiHOG000294085.
    HOVERGENiHBG104927.
    InParanoidiQ96BN8.
    KOiK18343.
    OMAiKYNTEEF.
    OrthoDBiEOG091G0BXG.
    PhylomeDBiQ96BN8.
    TreeFamiTF328709.

    Enzyme and pathway databases

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

    Miscellaneous databases

    GenomeRNAii90268.
    PROiQ96BN8.
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000154124.
    CleanExiHS_FAM105B.
    ExpressionAtlasiQ96BN8. baseline and differential.
    GenevisibleiQ96BN8. HS.

    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_HUMAN
    AccessioniPrimary (citable) accession number: Q96BN8
    Secondary accession number(s): D3DTD3, Q8NAS0, Q96IA3
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: November 28, 2006
    Last sequence update: November 28, 2006
    Last modified: November 30, 2016
    This is version 97 of the entry and version 3 of the sequence. [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, Reference proteome

    Documents

    1. Human chromosome 5
      Human chromosome 5: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. Peptidase families
      Classification of peptidase families and list of entries
    7. 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.