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Q96BN8 (OTUL_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 72. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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 names
Name:FAM105B
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length352 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.6 Ref.7 Ref.8 Ref.9

Catalytic activity

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). Ref.6 Ref.8

Subunit structure

Interacts with RNF31; the interaction is direct. Ref.9

Subcellular location

Cytoplasm Ref.8.

Domain

The specificity for linear polyubiquitin is given by the 'Glu-16' residue in ubiquitin chain (Ref.8).

Post-translational modification

Ubiquitinated. Ref.8

Acetylated. Ref.8

Phosphorylated. Ref.8

Sequence similarities

Belongs to the peptidase C65 family. Otulin subfamily.

Contains 1 OTU domain.

Biophysicochemical properties

Kinetic parameters:

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

KM=7.98 µM for linear diubiquitin Ref.8

Sequence caution

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.

Ontologies

Keywords
   Biological processAngiogenesis
Immunity
Innate immunity
Ubl conjugation pathway
Wnt signaling pathway
   Cellular componentCytoplasm
   Coding sequence diversityPolymorphism
   DomainCoiled coil
   Molecular functionHydrolase
Protease
Thiol protease
   PTMAcetylation
Phosphoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcanonical Wnt signaling pathway

Inferred from sequence or structural similarity. Source: UniProtKB

innate immune response

Inferred from mutant phenotype Ref.7. Source: UniProtKB

negative regulation of NF-kappaB transcription factor activity

Inferred from direct assay Ref.8. Source: UniProtKB

negative regulation of inflammatory response

Inferred from mutant phenotype Ref.7. Source: UniProtKB

nucleotide-binding oligomerization domain containing 2 signaling pathway

Inferred from mutant phenotype Ref.7. Source: UniProtKB

protein linear deubiquitination

Inferred from direct assay Ref.8Ref.7Ref.6. Source: UniProtKB

proteolysis

Inferred from electronic annotation. Source: UniProtKB-KW

sprouting angiogenesis

Inferred from sequence or structural similarity. Source: UniProtKB

   Cellular_componentLUBAC complex

Inferred from electronic annotation. Source: Ensembl

cytoplasm

Inferred from direct assay Ref.8. Source: UniProtKB

   Molecular_functioncysteine-type peptidase activity

Inferred from mutant phenotype Ref.8. Source: UniProtKB

ubiquitin-specific protease activity

Inferred from direct assay Ref.8Ref.7Ref.6. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 352352Ubiquitin thioesterase otulin
PRO_0000261637

Regions

Domain118 – 346229OTU
Region95 – 962Linear diubiquitin binding
Region124 – 1263Linear diubiquitin binding
Region255 – 2595Linear diubiquitin binding
Region283 – 2897Linear diubiquitin binding
Region336 – 3383Linear diubiquitin binding
Coiled coil49 – 7325 Potential

Sites

Active site1261 By similarity
Active site1291Nucleophile
Active site3391
Binding site3141Linear diubiquitin

Natural variations

Natural variant1551M → L.
Corresponds to variant rs11953822 [ dbSNP | Ensembl ].
VAR_053819
Natural variant2271S → N.
Corresponds to variant rs9312870 [ dbSNP | Ensembl ].
VAR_029469
Natural variant3111N → S.
Corresponds to variant rs9312870 [ dbSNP | Ensembl ].
VAR_053820

Experimental info

Mutagenesis911Y → F: Results in strong reduction of kcat while not affecting KM. Ref.8
Mutagenesis961W → A: Decreased activity toward linear ubiquitin. Ref.7 Ref.8
Mutagenesis100 – 1023TQK → AAA: Decreased activity toward linear ubiquitin. Ref.8
Mutagenesis1291C → A: Abolishes deubiquitinase activity. Ref.7 Ref.8 Ref.9
Mutagenesis2591L → E: Decreased affinity for linear diubiquitin. Ref.8
Mutagenesis3141E → R: Decreased affinity for linear diubiquitin. Ref.8
Mutagenesis3361D → A: Stabilizes H-339 in the active conformation, generating a more reactive enzyme. Ref.8
Mutagenesis3391H → A: Impaired deubiquitinase activity. Ref.8
Mutagenesis3411N → A: Abolishes deubiquitinase activity. Ref.8
Mutagenesis3411N → D: Stabilizes H-339 in the active conformation, generating a more reactive enzyme. Ref.8
Sequence conflict2111R → G in BAC03828. Ref.4

Secondary structure

............................................ 352
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q96BN8 [UniParc].

Last modified November 28, 2006. Version 3.
Checksum: 65071FF7B427C2FA

FASTA35240,263
        10         20         30         40         50         60 
MSRGTMPQPE AWPGASCAET PAREAAATAR DGGKAAASGQ PRPEMQCPAE HEEDMYRAAD 

        70         80         90        100        110        120 
EIEKEKELLI HERGASEPRL SVAPEMDIMD YCKKEWRGNT QKATCMKMGY EEVSQKFTSI 

       130        140        150        160        170        180 
RRVRGDNYCA LRATLFQAMS QAVGLPPWLQ DPELMLLPEK LISKYNWIKQ WKLGLKFDGK 

       190        200        210        220        230        240 
NEDLVDKIKE SLTLLRKKWA GLAEMRTAEA RQIACDELFT NEAEEYSLYE AVKFLMLNRA 

       250        260        270        280        290        300 
IELYNDKEKG KEVPFFSVLL FARDTSNDPG QLLRNHLNQV GHTGGLEQVE MFLLAYAVRH 

       310        320        330        340        350 
TIQVYRLSKY NTEEFITVYP TDPPKDWPVV TLIAEDDRHY NIPVRVCEET SL 

« Hide

References

« Hide 'large scale' references
[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. expand/collapse author list , 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]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
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. expand/collapse author list , 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]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
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]"OTULIN restricts Met1-linked ubiquitination to control innate immune signaling."
Fiil B.K., Damgaard R.B., Wagner S.A., Keusekotten K., Fritsch M., Bekker-Jensen S., Mailand N., Choudhary C., Komander D., Gyrd-Hansen M.
Mol. Cell 50:818-830(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, MUTAGENESIS OF TRP-96 AND CYS-129.
[8]"OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin."
Keusekotten K., Elliott P.R., Glockner L., Fiil B.K., Damgaard R.B., Kulathu Y., Wauer T., Hospenthal M.K., Gyrd-Hansen M., Krappmann D., Hofmann K., Komander D.
Cell 153:1312-1326(2013) [PubMed] [Europe PMC] [Abstract]
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]"The linear ubiquitin-specific deubiquitinase gumby regulates angiogenesis."
Rivkin E., Almeida S.M., Ceccarelli D.F., Juang Y.C., Maclean T.A., Srikumar T., Huang H., Dunham W.H., Fukumura R., Xie G., Gondo Y., Raught B., Gingras A.C., Sicheri F., Cordes S.P.
Nature 498:318-324(2013) [PubMed] [Europe PMC] [Abstract]
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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
RefSeqNP_612357.4. NM_138348.4.
UniGeneHs.406335.

3D structure databases

PDBe
RCSB PDB
PDBj
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[»]
ProteinModelPortalQ96BN8.
SMRQ96BN8. Positions 80-346.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid124684. 9 interactions.
IntActQ96BN8. 2 interactions.
MINTMINT-7944191.

PTM databases

PhosphoSiteQ96BN8.

Polymorphism databases

DMDM118572305.

Proteomic databases

PaxDbQ96BN8.
PeptideAtlasQ96BN8.
PRIDEQ96BN8.

Protocols and materials databases

DNASU90268.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000284274; ENSP00000284274; ENSG00000154124.
GeneID90268.
KEGGhsa:90268.
UCSCuc003jfk.3. human.

Organism-specific databases

CTD90268.
GeneCardsGC05P014666.
HGNCHGNC:25118. FAM105B.
HPAHPA051074.
neXtProtNX_Q96BN8.
PharmGKBPA142671789.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG47891.
HOGENOMHOG000294085.
HOVERGENHBG104927.
InParanoidQ96BN8.
OMAKYNTEEF.
PhylomeDBQ96BN8.
TreeFamTF328709.

Gene expression databases

ArrayExpressQ96BN8.
BgeeQ96BN8.
CleanExHS_FAM105B.
GenevestigatorQ96BN8.

Family and domain databases

InterProIPR023235. FAM105.
IPR023237. FAM105B.
[Graphical view]
PRINTSPR02055. PROTEINF105.
PR02057. PROTEINF105B.
ProtoNetSearch...

Other

ChiTaRSFAM105B. human.
GenomeRNAi90268.
NextBio76620.
PROQ96BN8.

Entry information

Entry nameOTUL_HUMAN
AccessionPrimary (citable) accession number: Q96BN8
Secondary accession number(s): D3DTD3, Q8NAS0, Q96IA3
Entry history
Integrated into UniProtKB/Swiss-Prot: November 28, 2006
Last sequence update: November 28, 2006
Last modified: April 16, 2014
This is version 72 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Peptidase families

Classification of peptidase families and list of entries

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 5

Human chromosome 5: entries, gene names and cross-references to MIM