Full text data of FAM105B
FAM105B
[Confidence: low (only semi-automatic identification from reviews)]
Ubiquitin thioesterase otulin; 3.4.19.12 (Deubiquitinating enzyme otulin; OTU domain-containing deubiquitinase with linear linkage specificity; Ubiquitin thioesterase Gumby)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Ubiquitin thioesterase otulin; 3.4.19.12 (Deubiquitinating enzyme otulin; OTU domain-containing deubiquitinase with linear linkage specificity; Ubiquitin thioesterase Gumby)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q96BN8
ID OTUL_HUMAN Reviewed; 352 AA.
AC Q96BN8; D3DTD3; Q8NAS0; Q96IA3;
DT 28-NOV-2006, integrated into UniProtKB/Swiss-Prot.
read moreDT 28-NOV-2006, sequence version 3.
DT 22-JAN-2014, entry version 70.
DE RecName: Full=Ubiquitin thioesterase otulin;
DE EC=3.4.19.12;
DE AltName: Full=Deubiquitinating enzyme otulin;
DE AltName: Full=OTU domain-containing deubiquitinase with linear linkage specificity;
DE AltName: Full=Ubiquitin thioesterase Gumby;
GN Name=FAM105B;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Ovary, and Prostate;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 123-298.
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [6]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=23827681; DOI=10.1016/j.cell.2013.05.046;
RA Mevissen T.E., Hospenthal M.K., Geurink P.P., Elliott P.R., Akutsu M.,
RA Arnaudo N., Ekkebus R., Kulathu Y., Wauer T., El Oualid F.,
RA Freund S.M., Ovaa H., Komander D.;
RT "OTU deubiquitinases reveal mechanisms of linkage specificity and
RT enable ubiquitin chain restriction analysis.";
RL Cell 154:169-184(2013).
RN [7]
RP FUNCTION, AND MUTAGENESIS OF TRP-96 AND CYS-129.
RX PubMed=23806334; DOI=10.1016/j.molcel.2013.06.004;
RA Fiil B.K., Damgaard R.B., Wagner S.A., Keusekotten K., Fritsch M.,
RA Bekker-Jensen S., Mailand N., Choudhary C., Komander D.,
RA Gyrd-Hansen M.;
RT "OTULIN restricts Met1-linked ubiquitination to control innate immune
RT signaling.";
RL Mol. Cell 50:818-830(2013).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (1.3 ANGSTROMS) OF MUTANT ASP-336, X-RAY
RP CRYSTALLOGRAPHY (1.35 ANGSTROMS) IN COMPLEX WITH LINEAR DIUBIQUITIN,
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES,
RP SUBCELLULAR LOCATION, PHOSPHORYLATION, UBIQUITINATION, ACETYLATION,
RP AND MUTAGENESIS OF TYR-91; TRP-96; 100-THR--LYS-102; CYS-129; LEU-259;
RP GLU-314; ASP-336; HIS-339 AND ASN-341.
RX PubMed=23746843; DOI=10.1016/j.cell.2013.05.014;
RA Keusekotten K., Elliott P.R., Glockner L., Fiil B.K., Damgaard R.B.,
RA Kulathu Y., Wauer T., Hospenthal M.K., Gyrd-Hansen M., Krappmann D.,
RA Hofmann K., Komander D.;
RT "OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-
RT linked polyubiquitin.";
RL Cell 153:1312-1326(2013).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 79-352 OF MUTANT CYS-129,
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 79-352 OF MUTANT CYS-129 IN
RP COMPLEX WITH LINEAR DIUBIQUITIN, FUNCTION, INTERACTION WITH RNF31 AND
RP DVL2, AND MUTAGENESIS OF CYS-129.
RX PubMed=23708998; DOI=10.1038/nature12296;
RA Rivkin E., Almeida S.M., Ceccarelli D.F., Juang Y.C., Maclean T.A.,
RA Srikumar T., Huang H., Dunham W.H., Fukumura R., Xie G., Gondo Y.,
RA Raught B., Gingras A.C., Sicheri F., Cordes S.P.;
RT "The linear ubiquitin-specific deubiquitinase gumby regulates
RT angiogenesis.";
RL Nature 498:318-324(2013).
CC -!- FUNCTION: Deubiquitinase that specifically removes linear ('Met-
CC 1'-linked) polyubiquitin chains to substrates and acts as a
CC regulator of angiogenesis and innate immune response. Associates
CC with the LUBAC complex via direct interaction with RNF31 and
CC counteracts its action by cleaving linear polyubiquitin chains to
CC substrates. Required during angiogenesis, craniofacial and
CC neuronal development by regulating the canonical Wnt signaling
CC together with the LUBAC complex. Acts as a negative regulator of
CC NF-kappa-B by counteracting activity of the LUBAC complex. Plays a
CC key role in innate immune response: required to restrict linear
CC polyubiquitin formation on RIPK2 in response to NOD2 stimulation,
CC probably to limit NOD2-dependent proinflammatory signaling.
CC -!- CATALYTIC ACTIVITY: Thiol-dependent hydrolysis of ester,
CC thioester, amide, peptide and isopeptide bonds formed by the C-
CC terminal Gly of ubiquitin (a 76-residue protein attached to
CC proteins as an intracellular targeting signal).
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=7.98 uM for linear diubiquitin;
CC Note=Kcat is 6.3 sec(-1) with linear diubiquitin as substrate;
CC -!- SUBUNIT: Interacts with RNF31; the interaction is direct.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- DOMAIN: The specificity for linear polyubiquitin is given by the
CC 'Glu-16' residue in ubiquitin chain (PubMed:23746843).
CC -!- PTM: Ubiquitinated.
CC -!- PTM: Acetylated.
CC -!- PTM: Phosphorylated.
CC -!- SIMILARITY: Belongs to the peptidase C65 family. Otulin subfamily.
CC -!- SIMILARITY: Contains 1 OTU domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH07706.3; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=AAH15392.2; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=BAC03828.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
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DR EMBL; AC010491; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471102; EAX08038.1; -; Genomic_DNA.
DR EMBL; CH471102; EAX08039.1; -; Genomic_DNA.
DR EMBL; BC007706; AAH07706.3; ALT_INIT; mRNA.
DR EMBL; BC015392; AAH15392.2; ALT_INIT; mRNA.
DR EMBL; AK092203; BAC03828.1; ALT_INIT; mRNA.
DR RefSeq; NP_612357.4; NM_138348.4.
DR UniGene; Hs.406335; -.
DR PDB; 3ZNV; X-ray; 1.30 A; A=80-352.
DR PDB; 3ZNX; X-ray; 1.35 A; A=80-352.
DR PDB; 3ZNZ; X-ray; 1.90 A; A=80-352.
DR PDB; 4KSJ; X-ray; 1.60 A; A=79-352.
DR PDB; 4KSK; X-ray; 2.40 A; A/B=55-352.
DR PDB; 4KSL; X-ray; 2.83 A; A/B/E/G/I/K/M/O/Q/S/U/W=79-352.
DR PDBsum; 3ZNV; -.
DR PDBsum; 3ZNX; -.
DR PDBsum; 3ZNZ; -.
DR PDBsum; 4KSJ; -.
DR PDBsum; 4KSK; -.
DR PDBsum; 4KSL; -.
DR ProteinModelPortal; Q96BN8; -.
DR SMR; Q96BN8; 80-346.
DR IntAct; Q96BN8; 2.
DR MINT; MINT-7944191; -.
DR PhosphoSite; Q96BN8; -.
DR DMDM; 118572305; -.
DR PaxDb; Q96BN8; -.
DR PeptideAtlas; Q96BN8; -.
DR PRIDE; Q96BN8; -.
DR DNASU; 90268; -.
DR Ensembl; ENST00000284274; ENSP00000284274; ENSG00000154124.
DR GeneID; 90268; -.
DR KEGG; hsa:90268; -.
DR UCSC; uc003jfk.3; human.
DR CTD; 90268; -.
DR GeneCards; GC05P014666; -.
DR HGNC; HGNC:25118; FAM105B.
DR HPA; HPA051074; -.
DR neXtProt; NX_Q96BN8; -.
DR PharmGKB; PA142671789; -.
DR eggNOG; NOG47891; -.
DR HOGENOM; HOG000294085; -.
DR HOVERGEN; HBG104927; -.
DR InParanoid; Q96BN8; -.
DR OMA; KYNTEEF; -.
DR ChiTaRS; FAM105B; human.
DR GenomeRNAi; 90268; -.
DR NextBio; 76620; -.
DR PRO; PR:Q96BN8; -.
DR ArrayExpress; Q96BN8; -.
DR Bgee; Q96BN8; -.
DR CleanEx; HS_FAM105B; -.
DR Genevestigator; Q96BN8; -.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0004843; F:deubiquitinase activity; IDA:UniProtKB.
DR GO; GO:0060070; P:canonical Wnt receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0045087; P:innate immune response; IMP:UniProtKB.
DR GO; GO:0050728; P:negative regulation of inflammatory response; IMP:UniProtKB.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IDA:UniProtKB.
DR GO; GO:0070431; P:nucleotide-binding oligomerization domain containing 2 signaling pathway; IMP:UniProtKB.
DR GO; GO:1990108; P:protein linear deubiquitination; IDA:UniProtKB.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR GO; GO:0002040; P:sprouting angiogenesis; ISS:UniProtKB.
DR InterPro; IPR023235; FAM105.
DR InterPro; IPR023237; FAM105B.
DR PRINTS; PR02055; PROTEINF105.
DR PRINTS; PR02057; PROTEINF105B.
DR PROSITE; PS50802; OTU; FALSE_NEG.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Angiogenesis; Coiled coil;
KW Complete proteome; Cytoplasm; Hydrolase; Immunity; Innate immunity;
KW Phosphoprotein; Polymorphism; Protease; Reference proteome;
KW Thiol protease; Ubl conjugation; Ubl conjugation pathway;
KW Wnt signaling pathway.
FT CHAIN 1 352 Ubiquitin thioesterase otulin.
FT /FTId=PRO_0000261637.
FT DOMAIN 118 346 OTU.
FT REGION 95 96 Linear diubiquitin binding.
FT REGION 124 126 Linear diubiquitin binding.
FT REGION 255 259 Linear diubiquitin binding.
FT REGION 283 289 Linear diubiquitin binding.
FT REGION 336 338 Linear diubiquitin binding.
FT COILED 49 73 Potential.
FT ACT_SITE 126 126 By similarity.
FT ACT_SITE 129 129 Nucleophile.
FT ACT_SITE 339 339
FT BINDING 314 314 Linear diubiquitin.
FT VARIANT 155 155 M -> L (in dbSNP:rs11953822).
FT /FTId=VAR_053819.
FT VARIANT 227 227 S -> N (in dbSNP:rs9312870).
FT /FTId=VAR_029469.
FT VARIANT 311 311 N -> S (in dbSNP:rs9312870).
FT /FTId=VAR_053820.
FT MUTAGEN 91 91 Y->F: Results in strong reduction of kcat
FT while not affecting KM.
FT MUTAGEN 96 96 W->A: Decreased activity toward linear
FT ubiquitin.
FT MUTAGEN 100 102 TQK->AAA: Decreased activity toward
FT linear ubiquitin.
FT MUTAGEN 129 129 C->A: Abolishes deubiquitinase activity.
FT MUTAGEN 259 259 L->E: Decreased affinity for linear
FT diubiquitin.
FT MUTAGEN 314 314 E->R: Decreased affinity for linear
FT diubiquitin.
FT MUTAGEN 336 336 D->A: Stabilizes H-339 in the active
FT conformation, generating a more reactive
FT enzyme.
FT MUTAGEN 339 339 H->A: Impaired deubiquitinase activity.
FT MUTAGEN 341 341 N->A: Abolishes deubiquitinase activity.
FT MUTAGEN 341 341 N->D: Stabilizes H-339 in the active
FT conformation, generating a more reactive
FT enzyme.
FT CONFLICT 211 211 R -> G (in Ref. 4; BAC03828).
FT HELIX 88 95
FT HELIX 101 114
FT STRAND 118 121
FT HELIX 129 140
FT HELIX 147 150
FT HELIX 153 164
FT HELIX 166 170
FT HELIX 184 204
FT HELIX 208 218
FT STRAND 220 222
FT HELIX 223 248
FT HELIX 255 262
FT STRAND 263 265
FT HELIX 269 275
FT HELIX 277 279
FT TURN 280 282
FT HELIX 288 298
FT STRAND 301 306
FT HELIX 307 309
FT HELIX 313 315
FT STRAND 316 322
FT STRAND 329 336
FT STRAND 339 344
FT HELIX 346 348
SQ SEQUENCE 352 AA; 40263 MW; 65071FF7B427C2FA CRC64;
MSRGTMPQPE AWPGASCAET PAREAAATAR DGGKAAASGQ PRPEMQCPAE HEEDMYRAAD
EIEKEKELLI HERGASEPRL SVAPEMDIMD YCKKEWRGNT QKATCMKMGY EEVSQKFTSI
RRVRGDNYCA LRATLFQAMS QAVGLPPWLQ DPELMLLPEK LISKYNWIKQ WKLGLKFDGK
NEDLVDKIKE SLTLLRKKWA GLAEMRTAEA RQIACDELFT NEAEEYSLYE AVKFLMLNRA
IELYNDKEKG KEVPFFSVLL FARDTSNDPG QLLRNHLNQV GHTGGLEQVE MFLLAYAVRH
TIQVYRLSKY NTEEFITVYP TDPPKDWPVV TLIAEDDRHY NIPVRVCEET SL
//
ID OTUL_HUMAN Reviewed; 352 AA.
AC Q96BN8; D3DTD3; Q8NAS0; Q96IA3;
DT 28-NOV-2006, integrated into UniProtKB/Swiss-Prot.
read moreDT 28-NOV-2006, sequence version 3.
DT 22-JAN-2014, entry version 70.
DE RecName: Full=Ubiquitin thioesterase otulin;
DE EC=3.4.19.12;
DE AltName: Full=Deubiquitinating enzyme otulin;
DE AltName: Full=OTU domain-containing deubiquitinase with linear linkage specificity;
DE AltName: Full=Ubiquitin thioesterase Gumby;
GN Name=FAM105B;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Ovary, and Prostate;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 123-298.
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [6]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=23827681; DOI=10.1016/j.cell.2013.05.046;
RA Mevissen T.E., Hospenthal M.K., Geurink P.P., Elliott P.R., Akutsu M.,
RA Arnaudo N., Ekkebus R., Kulathu Y., Wauer T., El Oualid F.,
RA Freund S.M., Ovaa H., Komander D.;
RT "OTU deubiquitinases reveal mechanisms of linkage specificity and
RT enable ubiquitin chain restriction analysis.";
RL Cell 154:169-184(2013).
RN [7]
RP FUNCTION, AND MUTAGENESIS OF TRP-96 AND CYS-129.
RX PubMed=23806334; DOI=10.1016/j.molcel.2013.06.004;
RA Fiil B.K., Damgaard R.B., Wagner S.A., Keusekotten K., Fritsch M.,
RA Bekker-Jensen S., Mailand N., Choudhary C., Komander D.,
RA Gyrd-Hansen M.;
RT "OTULIN restricts Met1-linked ubiquitination to control innate immune
RT signaling.";
RL Mol. Cell 50:818-830(2013).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (1.3 ANGSTROMS) OF MUTANT ASP-336, X-RAY
RP CRYSTALLOGRAPHY (1.35 ANGSTROMS) IN COMPLEX WITH LINEAR DIUBIQUITIN,
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES,
RP SUBCELLULAR LOCATION, PHOSPHORYLATION, UBIQUITINATION, ACETYLATION,
RP AND MUTAGENESIS OF TYR-91; TRP-96; 100-THR--LYS-102; CYS-129; LEU-259;
RP GLU-314; ASP-336; HIS-339 AND ASN-341.
RX PubMed=23746843; DOI=10.1016/j.cell.2013.05.014;
RA Keusekotten K., Elliott P.R., Glockner L., Fiil B.K., Damgaard R.B.,
RA Kulathu Y., Wauer T., Hospenthal M.K., Gyrd-Hansen M., Krappmann D.,
RA Hofmann K., Komander D.;
RT "OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-
RT linked polyubiquitin.";
RL Cell 153:1312-1326(2013).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 79-352 OF MUTANT CYS-129,
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 79-352 OF MUTANT CYS-129 IN
RP COMPLEX WITH LINEAR DIUBIQUITIN, FUNCTION, INTERACTION WITH RNF31 AND
RP DVL2, AND MUTAGENESIS OF CYS-129.
RX PubMed=23708998; DOI=10.1038/nature12296;
RA Rivkin E., Almeida S.M., Ceccarelli D.F., Juang Y.C., Maclean T.A.,
RA Srikumar T., Huang H., Dunham W.H., Fukumura R., Xie G., Gondo Y.,
RA Raught B., Gingras A.C., Sicheri F., Cordes S.P.;
RT "The linear ubiquitin-specific deubiquitinase gumby regulates
RT angiogenesis.";
RL Nature 498:318-324(2013).
CC -!- FUNCTION: Deubiquitinase that specifically removes linear ('Met-
CC 1'-linked) polyubiquitin chains to substrates and acts as a
CC regulator of angiogenesis and innate immune response. Associates
CC with the LUBAC complex via direct interaction with RNF31 and
CC counteracts its action by cleaving linear polyubiquitin chains to
CC substrates. Required during angiogenesis, craniofacial and
CC neuronal development by regulating the canonical Wnt signaling
CC together with the LUBAC complex. Acts as a negative regulator of
CC NF-kappa-B by counteracting activity of the LUBAC complex. Plays a
CC key role in innate immune response: required to restrict linear
CC polyubiquitin formation on RIPK2 in response to NOD2 stimulation,
CC probably to limit NOD2-dependent proinflammatory signaling.
CC -!- CATALYTIC ACTIVITY: Thiol-dependent hydrolysis of ester,
CC thioester, amide, peptide and isopeptide bonds formed by the C-
CC terminal Gly of ubiquitin (a 76-residue protein attached to
CC proteins as an intracellular targeting signal).
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=7.98 uM for linear diubiquitin;
CC Note=Kcat is 6.3 sec(-1) with linear diubiquitin as substrate;
CC -!- SUBUNIT: Interacts with RNF31; the interaction is direct.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- DOMAIN: The specificity for linear polyubiquitin is given by the
CC 'Glu-16' residue in ubiquitin chain (PubMed:23746843).
CC -!- PTM: Ubiquitinated.
CC -!- PTM: Acetylated.
CC -!- PTM: Phosphorylated.
CC -!- SIMILARITY: Belongs to the peptidase C65 family. Otulin subfamily.
CC -!- SIMILARITY: Contains 1 OTU domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH07706.3; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=AAH15392.2; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=BAC03828.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
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DR EMBL; AC010491; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471102; EAX08038.1; -; Genomic_DNA.
DR EMBL; CH471102; EAX08039.1; -; Genomic_DNA.
DR EMBL; BC007706; AAH07706.3; ALT_INIT; mRNA.
DR EMBL; BC015392; AAH15392.2; ALT_INIT; mRNA.
DR EMBL; AK092203; BAC03828.1; ALT_INIT; mRNA.
DR RefSeq; NP_612357.4; NM_138348.4.
DR UniGene; Hs.406335; -.
DR PDB; 3ZNV; X-ray; 1.30 A; A=80-352.
DR PDB; 3ZNX; X-ray; 1.35 A; A=80-352.
DR PDB; 3ZNZ; X-ray; 1.90 A; A=80-352.
DR PDB; 4KSJ; X-ray; 1.60 A; A=79-352.
DR PDB; 4KSK; X-ray; 2.40 A; A/B=55-352.
DR PDB; 4KSL; X-ray; 2.83 A; A/B/E/G/I/K/M/O/Q/S/U/W=79-352.
DR PDBsum; 3ZNV; -.
DR PDBsum; 3ZNX; -.
DR PDBsum; 3ZNZ; -.
DR PDBsum; 4KSJ; -.
DR PDBsum; 4KSK; -.
DR PDBsum; 4KSL; -.
DR ProteinModelPortal; Q96BN8; -.
DR SMR; Q96BN8; 80-346.
DR IntAct; Q96BN8; 2.
DR MINT; MINT-7944191; -.
DR PhosphoSite; Q96BN8; -.
DR DMDM; 118572305; -.
DR PaxDb; Q96BN8; -.
DR PeptideAtlas; Q96BN8; -.
DR PRIDE; Q96BN8; -.
DR DNASU; 90268; -.
DR Ensembl; ENST00000284274; ENSP00000284274; ENSG00000154124.
DR GeneID; 90268; -.
DR KEGG; hsa:90268; -.
DR UCSC; uc003jfk.3; human.
DR CTD; 90268; -.
DR GeneCards; GC05P014666; -.
DR HGNC; HGNC:25118; FAM105B.
DR HPA; HPA051074; -.
DR neXtProt; NX_Q96BN8; -.
DR PharmGKB; PA142671789; -.
DR eggNOG; NOG47891; -.
DR HOGENOM; HOG000294085; -.
DR HOVERGEN; HBG104927; -.
DR InParanoid; Q96BN8; -.
DR OMA; KYNTEEF; -.
DR ChiTaRS; FAM105B; human.
DR GenomeRNAi; 90268; -.
DR NextBio; 76620; -.
DR PRO; PR:Q96BN8; -.
DR ArrayExpress; Q96BN8; -.
DR Bgee; Q96BN8; -.
DR CleanEx; HS_FAM105B; -.
DR Genevestigator; Q96BN8; -.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0004843; F:deubiquitinase activity; IDA:UniProtKB.
DR GO; GO:0060070; P:canonical Wnt receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0045087; P:innate immune response; IMP:UniProtKB.
DR GO; GO:0050728; P:negative regulation of inflammatory response; IMP:UniProtKB.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IDA:UniProtKB.
DR GO; GO:0070431; P:nucleotide-binding oligomerization domain containing 2 signaling pathway; IMP:UniProtKB.
DR GO; GO:1990108; P:protein linear deubiquitination; IDA:UniProtKB.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR GO; GO:0002040; P:sprouting angiogenesis; ISS:UniProtKB.
DR InterPro; IPR023235; FAM105.
DR InterPro; IPR023237; FAM105B.
DR PRINTS; PR02055; PROTEINF105.
DR PRINTS; PR02057; PROTEINF105B.
DR PROSITE; PS50802; OTU; FALSE_NEG.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Angiogenesis; Coiled coil;
KW Complete proteome; Cytoplasm; Hydrolase; Immunity; Innate immunity;
KW Phosphoprotein; Polymorphism; Protease; Reference proteome;
KW Thiol protease; Ubl conjugation; Ubl conjugation pathway;
KW Wnt signaling pathway.
FT CHAIN 1 352 Ubiquitin thioesterase otulin.
FT /FTId=PRO_0000261637.
FT DOMAIN 118 346 OTU.
FT REGION 95 96 Linear diubiquitin binding.
FT REGION 124 126 Linear diubiquitin binding.
FT REGION 255 259 Linear diubiquitin binding.
FT REGION 283 289 Linear diubiquitin binding.
FT REGION 336 338 Linear diubiquitin binding.
FT COILED 49 73 Potential.
FT ACT_SITE 126 126 By similarity.
FT ACT_SITE 129 129 Nucleophile.
FT ACT_SITE 339 339
FT BINDING 314 314 Linear diubiquitin.
FT VARIANT 155 155 M -> L (in dbSNP:rs11953822).
FT /FTId=VAR_053819.
FT VARIANT 227 227 S -> N (in dbSNP:rs9312870).
FT /FTId=VAR_029469.
FT VARIANT 311 311 N -> S (in dbSNP:rs9312870).
FT /FTId=VAR_053820.
FT MUTAGEN 91 91 Y->F: Results in strong reduction of kcat
FT while not affecting KM.
FT MUTAGEN 96 96 W->A: Decreased activity toward linear
FT ubiquitin.
FT MUTAGEN 100 102 TQK->AAA: Decreased activity toward
FT linear ubiquitin.
FT MUTAGEN 129 129 C->A: Abolishes deubiquitinase activity.
FT MUTAGEN 259 259 L->E: Decreased affinity for linear
FT diubiquitin.
FT MUTAGEN 314 314 E->R: Decreased affinity for linear
FT diubiquitin.
FT MUTAGEN 336 336 D->A: Stabilizes H-339 in the active
FT conformation, generating a more reactive
FT enzyme.
FT MUTAGEN 339 339 H->A: Impaired deubiquitinase activity.
FT MUTAGEN 341 341 N->A: Abolishes deubiquitinase activity.
FT MUTAGEN 341 341 N->D: Stabilizes H-339 in the active
FT conformation, generating a more reactive
FT enzyme.
FT CONFLICT 211 211 R -> G (in Ref. 4; BAC03828).
FT HELIX 88 95
FT HELIX 101 114
FT STRAND 118 121
FT HELIX 129 140
FT HELIX 147 150
FT HELIX 153 164
FT HELIX 166 170
FT HELIX 184 204
FT HELIX 208 218
FT STRAND 220 222
FT HELIX 223 248
FT HELIX 255 262
FT STRAND 263 265
FT HELIX 269 275
FT HELIX 277 279
FT TURN 280 282
FT HELIX 288 298
FT STRAND 301 306
FT HELIX 307 309
FT HELIX 313 315
FT STRAND 316 322
FT STRAND 329 336
FT STRAND 339 344
FT HELIX 346 348
SQ SEQUENCE 352 AA; 40263 MW; 65071FF7B427C2FA CRC64;
MSRGTMPQPE AWPGASCAET PAREAAATAR DGGKAAASGQ PRPEMQCPAE HEEDMYRAAD
EIEKEKELLI HERGASEPRL SVAPEMDIMD YCKKEWRGNT QKATCMKMGY EEVSQKFTSI
RRVRGDNYCA LRATLFQAMS QAVGLPPWLQ DPELMLLPEK LISKYNWIKQ WKLGLKFDGK
NEDLVDKIKE SLTLLRKKWA GLAEMRTAEA RQIACDELFT NEAEEYSLYE AVKFLMLNRA
IELYNDKEKG KEVPFFSVLL FARDTSNDPG QLLRNHLNQV GHTGGLEQVE MFLLAYAVRH
TIQVYRLSKY NTEEFITVYP TDPPKDWPVV TLIAEDDRHY NIPVRVCEET SL
//