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Q96BN8

- OTUL_HUMAN

UniProt

Q96BN8 - OTUL_HUMAN

Protein

Ubiquitin thioesterase otulin

Gene

OTULIN

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 77 (01 Oct 2014)
      Sequence version 3 (28 Nov 2006)
      Previous versions | rss
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    Functioni

    Deubiquitinase that specifically removes linear ('Met-1'-linked) polyubiquitin chains to substrates and acts as a regulator of angiogenesis and innate immune response. Associates with the LUBAC complex via direct interaction with RNF31 and counteracts its action by cleaving linear polyubiquitin chains to substrates. Required during angiogenesis, craniofacial and neuronal development by regulating the canonical Wnt signaling together with the LUBAC complex. Acts as a negative regulator of NF-kappa-B by counteracting activity of the LUBAC complex. Plays a key role in innate immune response: required to restrict linear polyubiquitin formation on RIPK2 in response to NOD2 stimulation, probably to limit NOD2-dependent proinflammatory signaling.4 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

    Kineticsi

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

    1. KM=7.98 µM for linear diubiquitin1 Publication

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Active sitei126 – 1261By similarity
    Active sitei129 – 1291Nucleophile
    Binding sitei314 – 3141Linear diubiquitin2 Publications
    Active sitei339 – 3391

    GO - Molecular functioni

    1. cysteine-type peptidase activity Source: UniProtKB
    2. protein binding Source: UniProtKB
    3. ubiquitin-specific protease activity Source: UniProtKB

    GO - Biological processi

    1. canonical Wnt signaling pathway Source: UniProtKB
    2. innate immune response Source: UniProtKB
    3. negative regulation of inflammatory response Source: UniProtKB
    4. negative regulation of NF-kappaB transcription factor activity Source: UniProtKB
    5. nucleotide-binding oligomerization domain containing 2 signaling pathway Source: UniProtKB
    6. protein linear deubiquitination Source: UniProtKB
    7. sprouting angiogenesis Source: UniProtKB

    Keywords - Molecular functioni

    Hydrolase, Protease, Thiol protease

    Keywords - Biological processi

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

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Ubiquitin thioesterase otulin (EC:3.4.19.12)
    Alternative name(s):
    Deubiquitinating enzyme otulin
    OTU domain-containing deubiquitinase with linear linkage specificity
    Ubiquitin thioesterase Gumby
    Gene namesi
    Name:OTULIN
    Synonyms:FAM105B
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 5

    Organism-specific databases

    HGNCiHGNC:25118. OTULIN.

    Subcellular locationi

    Cytoplasm 1 Publication

    GO - Cellular componenti

    1. cytoplasm Source: UniProtKB
    2. LUBAC complex Source: Ensembl

    Keywords - Cellular componenti

    Cytoplasm

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi91 – 911Y → F: Results in strong reduction of kcat while not affecting KM. 1 Publication
    Mutagenesisi96 – 961W → A: Decreased activity toward linear ubiquitin. 2 Publications
    Mutagenesisi100 – 1023TQK → AAA: Decreased activity toward linear ubiquitin.
    Mutagenesisi129 – 1291C → A: Abolishes deubiquitinase activity. 3 Publications
    Mutagenesisi259 – 2591L → E: Decreased affinity for linear diubiquitin. 1 Publication
    Mutagenesisi314 – 3141E → R: Decreased affinity for linear diubiquitin. 1 Publication
    Mutagenesisi336 – 3361D → A: Stabilizes H-339 in the active conformation, generating a more reactive enzyme. 1 Publication
    Mutagenesisi339 – 3391H → A: Impaired deubiquitinase activity. 1 Publication
    Mutagenesisi341 – 3411N → A: Abolishes deubiquitinase activity. 1 Publication
    Mutagenesisi341 – 3411N → D: Stabilizes H-339 in the active conformation, generating a more reactive enzyme. 1 Publication

    Organism-specific databases

    PharmGKBiPA142671789.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 352352Ubiquitin thioesterase otulinPRO_0000261637Add
    BLAST

    Post-translational modificationi

    Ubiquitinated.1 Publication
    Acetylated.1 Publication
    Phosphorylated.1 Publication

    Keywords - PTMi

    Acetylation, Phosphoprotein, Ubl conjugation

    Proteomic databases

    MaxQBiQ96BN8.
    PaxDbiQ96BN8.
    PeptideAtlasiQ96BN8.
    PRIDEiQ96BN8.

    PTM databases

    PhosphoSiteiQ96BN8.

    Expressioni

    Gene expression databases

    ArrayExpressiQ96BN8.
    BgeeiQ96BN8.
    CleanExiHS_FAM105B.
    GenevestigatoriQ96BN8.

    Organism-specific databases

    HPAiHPA051074.

    Interactioni

    Subunit structurei

    Interacts with RNF31; the interaction is direct.2 Publications

    Protein-protein interaction databases

    BioGridi124684. 11 interactions.
    IntActiQ96BN8. 2 interactions.
    MINTiMINT-7944191.

    Structurei

    Secondary structure

    1
    352
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi55 – 573
    Helixi59 – 635
    Helixi88 – 958
    Helixi101 – 11414
    Beta strandi118 – 1214
    Helixi129 – 14012
    Helixi147 – 1504
    Helixi153 – 16412
    Helixi166 – 1705
    Helixi184 – 20421
    Helixi208 – 21811
    Beta strandi220 – 2223
    Helixi223 – 24826
    Helixi255 – 2628
    Beta strandi263 – 2653
    Helixi269 – 2757
    Helixi277 – 2793
    Turni280 – 2823
    Helixi288 – 29811
    Beta strandi301 – 3066
    Helixi307 – 3093
    Helixi313 – 3153
    Beta strandi316 – 3227
    Beta strandi329 – 3368
    Beta strandi339 – 3446
    Helixi346 – 3483

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    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. Positions 80-346.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini118 – 346229OTUAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni95 – 962Linear diubiquitin binding
    Regioni124 – 1263Linear diubiquitin binding
    Regioni255 – 2595Linear diubiquitin binding
    Regioni283 – 2897Linear diubiquitin binding
    Regioni336 – 3383Linear diubiquitin binding

    Coiled coil

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Coiled coili49 – 7325Sequence AnalysisAdd
    BLAST

    Domaini

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

    Sequence similaritiesi

    Belongs to the peptidase C65 family. Otulin subfamily.Curated
    Contains 1 OTU domain.Curated

    Keywords - Domaini

    Coiled coil

    Phylogenomic databases

    eggNOGiNOG47891.
    HOGENOMiHOG000294085.
    HOVERGENiHBG104927.
    InParanoidiQ96BN8.
    KOiK18343.
    OMAiKYNTEEF.
    PhylomeDBiQ96BN8.
    TreeFamiTF328709.

    Family and domain databases

    InterProiIPR023235. FAM105.
    IPR023237. FAM105B.
    [Graphical view]
    PRINTSiPR02055. PROTEINF105.
    PR02057. PROTEINF105B.

    Sequencei

    Sequence statusi: Complete.

    Q96BN8-1 [UniParc]FASTAAdd to Basket

    « Hide

    MSRGTMPQPE AWPGASCAET PAREAAATAR DGGKAAASGQ PRPEMQCPAE    50
    HEEDMYRAAD EIEKEKELLI HERGASEPRL SVAPEMDIMD YCKKEWRGNT 100
    QKATCMKMGY EEVSQKFTSI RRVRGDNYCA LRATLFQAMS QAVGLPPWLQ 150
    DPELMLLPEK LISKYNWIKQ WKLGLKFDGK NEDLVDKIKE SLTLLRKKWA 200
    GLAEMRTAEA RQIACDELFT NEAEEYSLYE AVKFLMLNRA IELYNDKEKG 250
    KEVPFFSVLL FARDTSNDPG QLLRNHLNQV GHTGGLEQVE MFLLAYAVRH 300
    TIQVYRLSKY NTEEFITVYP TDPPKDWPVV TLIAEDDRHY NIPVRVCEET 350
    SL 352
    Length:352
    Mass (Da):40,263
    Last modified:November 28, 2006 - v3
    Checksum:i65071FF7B427C2FA
    GO

    Sequence cautioni

    The sequence AAH07706.3 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.
    The sequence AAH15392.2 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.
    The sequence BAC03828.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti211 – 2111R → G in BAC03828. (PubMed:14702039)Curated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti155 – 1551M → L.
    Corresponds to variant rs11953822 [ dbSNP | Ensembl ].
    VAR_053819
    Natural varianti227 – 2271S → N.
    Corresponds to variant rs9312870 [ dbSNP | Ensembl ].
    VAR_029469
    Natural varianti311 – 3111N → S.
    Corresponds to variant rs9312870 [ dbSNP | Ensembl ].
    VAR_053820

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    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_138348.4.
    UniGeneiHs.406335.

    Genome annotation databases

    EnsembliENST00000284274; ENSP00000284274; ENSG00000154124.
    GeneIDi90268.
    KEGGihsa:90268.
    UCSCiuc003jfk.3. human.

    Polymorphism databases

    DMDMi118572305.

    Keywords - Coding sequence diversityi

    Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    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.
    CCDSi CCDS43302.1.
    RefSeqi NP_612357.4. NM_138348.4.
    UniGenei Hs.406335.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    3ZNV X-ray 1.30 A 80-352 [» ]
    3ZNX X-ray 1.35 A 80-352 [» ]
    3ZNZ X-ray 1.90 A 80-352 [» ]
    4KSJ X-ray 1.60 A 79-352 [» ]
    4KSK X-ray 2.40 A/B 55-352 [» ]
    4KSL X-ray 2.83 A/B/E/G/I/K/M/O/Q/S/U/W 79-352 [» ]
    4OYK X-ray 2.00 C/D 49-67 [» ]
    4P0B X-ray 2.70 B/D 52-61 [» ]
    ProteinModelPortali Q96BN8.
    SMRi Q96BN8. Positions 80-346.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 124684. 11 interactions.
    IntActi Q96BN8. 2 interactions.
    MINTi MINT-7944191.

    PTM databases

    PhosphoSitei Q96BN8.

    Polymorphism databases

    DMDMi 118572305.

    Proteomic databases

    MaxQBi Q96BN8.
    PaxDbi Q96BN8.
    PeptideAtlasi Q96BN8.
    PRIDEi Q96BN8.

    Protocols and materials databases

    DNASUi 90268.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000284274 ; ENSP00000284274 ; ENSG00000154124 .
    GeneIDi 90268.
    KEGGi hsa:90268.
    UCSCi uc003jfk.3. human.

    Organism-specific databases

    CTDi 90268.
    GeneCardsi GC05P014666.
    HGNCi HGNC:25118. OTULIN.
    HPAi HPA051074.
    neXtProti NX_Q96BN8.
    PharmGKBi PA142671789.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi NOG47891.
    HOGENOMi HOG000294085.
    HOVERGENi HBG104927.
    InParanoidi Q96BN8.
    KOi K18343.
    OMAi KYNTEEF.
    PhylomeDBi Q96BN8.
    TreeFami TF328709.

    Miscellaneous databases

    ChiTaRSi FAM105B. human.
    GenomeRNAii 90268.
    NextBioi 76620.
    PROi Q96BN8.

    Gene expression databases

    ArrayExpressi Q96BN8.
    Bgeei Q96BN8.
    CleanExi HS_FAM105B.
    Genevestigatori Q96BN8.

    Family and domain databases

    InterProi IPR023235. FAM105.
    IPR023237. FAM105B.
    [Graphical view ]
    PRINTSi PR02055. PROTEINF105.
    PR02057. PROTEINF105B.
    ProtoNeti Search...

    Publicationsi

    1. "The DNA sequence and comparative analysis of human chromosome 5."
      Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.
      , Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.
      Nature 431:268-274(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    2. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    3. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
      Tissue: Ovary and Prostate.
    4. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
      Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
      , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
      Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 123-298.
    5. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    6. "OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis."
      Mevissen T.E., Hospenthal M.K., Geurink P.P., Elliott P.R., Akutsu M., Arnaudo N., Ekkebus R., Kulathu Y., Wauer T., El Oualid F., Freund S.M., Ovaa H., Komander D.
      Cell 154:169-184(2013) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, CATALYTIC ACTIVITY.
    7. Cited for: FUNCTION, MUTAGENESIS OF TRP-96 AND CYS-129.
    8. Cited for: X-RAY CRYSTALLOGRAPHY (1.3 ANGSTROMS) OF MUTANT ASP-336, X-RAY CRYSTALLOGRAPHY (1.35 ANGSTROMS) IN COMPLEX WITH LINEAR DIUBIQUITIN, FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, SUBCELLULAR LOCATION, PHOSPHORYLATION, UBIQUITINATION, ACETYLATION, MUTAGENESIS OF TYR-91; TRP-96; 100-THR--LYS-102; CYS-129; LEU-259; GLU-314; ASP-336; HIS-339 AND ASN-341.
    9. Cited for: X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 79-352 OF MUTANT CYS-129, X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 79-352 OF MUTANT CYS-129 IN COMPLEX WITH LINEAR DIUBIQUITIN, FUNCTION, INTERACTION WITH RNF31 AND DVL2, MUTAGENESIS OF CYS-129.

    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: October 1, 2014
    This is version 77 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. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    5. Peptidase families
      Classification of peptidase families and list of entries
    6. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3