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Protein

Ubiquitin thioesterase otulin

Gene

OTULIN

Organism
Homo sapiens (Human)
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: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
  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
    • protein ubiquitination Source: Reactome
    • regulation of tumor necrosis factor-mediated signaling pathway Source: UniProtKB
    • sprouting angiogenesis Source: UniProtKB

    Keywordsi

    Molecular functionHydrolase, Protease, Thiol protease
    Biological processAngiogenesis, 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

    EuPathDBiHostDB:ENSG00000154124.4
    HGNCiHGNC:25118 OTULIN
    MIMi615712 gene
    neXtProtiNX_Q96BN8

    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

    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
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_076865244Y → C in AIPDS; slightly impaired ability to mediate deubiquitination of linear polyubiquitin chains; does not affect ability to interact with RNF31. 1 PublicationCorresponds to variant dbSNP:rs886037887Ensembl.1
    Natural variantiVAR_076866272L → P in AIPDS; 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 PublicationsCorresponds to variant dbSNP:rs886037885Ensembl.1

    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
    MalaCardsiOTULIN
    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

    Show more details

    Protein-protein interaction databases

    BioGridi12468435 interactors.
    IntActiQ96BN8 10 interactors.
    MINTiQ96BN8
    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[»]
    5OE7X-ray2.95A80-350[»]
    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

    Phylogenomic databases

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

    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 dbSNP:rs11953822Ensembl.1
    Natural variantiVAR_029469227S → N. Corresponds to variant dbSNP:rs9312870Ensembl.1
    Natural variantiVAR_076865244Y → C in AIPDS; slightly impaired ability to mediate deubiquitination of linear polyubiquitin chains; does not affect ability to interact with RNF31. 1 PublicationCorresponds to variant dbSNP:rs886037887Ensembl.1
    Natural variantiVAR_076866272L → P in AIPDS; 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 PublicationsCorresponds to variant dbSNP:rs886037885Ensembl.1
    Natural variantiVAR_053820311N → S. Corresponds to variant dbSNP:rs9312870Ensembl.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

    Similar proteinsi

    Entry informationi

    Entry nameiOTUL_HUMAN
    AccessioniPrimary (citable) accession number: Q96BN8
    Secondary accession number(s): D3DTD3, Q8NAS0, Q96IA3
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 28, 2006
    Last sequence update: November 28, 2006
    Last modified: April 25, 2018
    This is version 108 of the entry and version 3 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, Reference proteome