Full text data of UBB
UBB
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Polyubiquitin-B; Ubiquitin; Flags: Precursor
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Polyubiquitin-B; Ubiquitin; Flags: Precursor
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P0CG47
ID UBB_HUMAN Reviewed; 229 AA.
AC P0CG47; P02248; P02249; P02250; P62988; Q29120; Q6LBL4; Q6LDU5;
read moreAC Q8WYN8; Q91887; Q91888; Q9BWD6; Q9BX98; Q9UEF2; Q9UEG1; Q9UEK8;
AC Q9UPK7;
DT 10-AUG-2010, integrated into UniProtKB/Swiss-Prot.
DT 10-AUG-2010, sequence version 1.
DT 22-JAN-2014, entry version 38.
DE RecName: Full=Polyubiquitin-B;
DE Contains:
DE RecName: Full=Ubiquitin;
DE Flags: Precursor;
GN Name=UBB;
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 [GENOMIC DNA].
RC TISSUE=Blood;
RX PubMed=3029682; DOI=10.1093/nar/15.2.443;
RA Baker R.T., Board P.G.;
RT "The human ubiquitin gene family: structure of a gene and pseudogenes
RT from the Ub B subfamily.";
RL Nucleic Acids Res. 15:443-463(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=14745543; DOI=10.1007/s00239-003-2532-4;
RA Tachikui H., Saitou N., Nakajima T., Hayasaka I., Ishida T., Inoue I.;
RT "Lineage-specific homogenization of the polyubiquitin gene among human
RT and great apes.";
RL J. Mol. Evol. 57:737-744(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R.,
RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N.,
RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B.,
RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J.,
RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E.,
RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J.,
RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C.,
RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in
RT the human lineage.";
RL Nature 440:1045-1049(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, Liver, and Lung;
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 [5]
RP PROTEIN SEQUENCE OF 1-27; 30-42 AND 55-72, AND MASS SPECTROMETRY.
RC TISSUE=Fetal brain cortex;
RA Lubec G., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [6]
RP PROTEIN SEQUENCE OF 1-74.
RX PubMed=124018; DOI=10.1038/255423a0;
RA Schlesinger D.H., Goldstein G.;
RT "Hybrid troponin reconstituted from vertebrate and arthropod
RT subunits.";
RL Nature 255:423-424(1975).
RN [7]
RP PROTEIN SEQUENCE OF 1-27 AND 43-54, UBIQUITINATION AT LYS-6; LYS-11
RP AND LYS-48, AND MASS SPECTROMETRY.
RX PubMed=16443603; DOI=10.1074/jbc.M512786200;
RA Cripps D., Thomas S.N., Jeng Y., Yang F., Davies P., Yang A.J.;
RT "Alzheimer disease-specific conformation of hyperphosphorylated paired
RT helical filament-tau is polyubiquitinated through Lys-48, Lys-11, and
RT Lys-6 ubiquitin conjugation.";
RL J. Biol. Chem. 281:10825-10838(2006).
RN [8]
RP FUNCTION, UBIQUITINATION AT LYS-11; LYS-29; LYS-48 AND LYS-63, AND
RP MASS SPECTROMETRY.
RX PubMed=16543144; DOI=10.1016/j.molcel.2006.02.018;
RA Huang F., Kirkpatrick D., Jiang X., Gygi S.P., Sorkin A.;
RT "Differential regulation of EGF receptor internalization and
RT degradation by multiubiquitination within the kinase domain.";
RL Mol. Cell 21:737-748(2006).
RN [9]
RP UBIQUITINATION AT LYS-27.
RX PubMed=15466860; DOI=10.1074/jbc.M402916200;
RA Okumura F., Hatakeyama S., Matsumoto M., Kamura T., Nakayama K.;
RT "Functional regulation of FEZ1 by the U-box-type ubiquitin ligase E4B
RT contributes to neuritogenesis.";
RL J. Biol. Chem. 279:53533-53543(2004).
RN [10]
RP UBIQUITINATION [LARGE SCALE ANALYSIS] AT LYS-48, AND MASS
RP SPECTROMETRY.
RC TISSUE=Lung adenocarcinoma;
RX PubMed=17203973; DOI=10.1021/pr060438j;
RA Vasilescu J., Zweitzig D.R., Denis N.J., Smith J.C., Ethier M.,
RA Haines D.S., Figeys D.;
RT "The proteomic reactor facilitates the analysis of affinity-purified
RT proteins by mass spectrometry: application for identifying
RT ubiquitinated proteins in human cells.";
RL J. Proteome Res. 6:298-305(2007).
RN [11]
RP UBIQUITINATION AT LYS-63, AND MUTAGENESIS OF LYS-48 AND LYS-63.
RX PubMed=18719106; DOI=10.1073/pnas.0805685105;
RA Motegi A., Liaw H.-J., Lee K.-Y., Roest H.P., Maas A., Wu X.,
RA Moinova H., Markowitz S.D., Ding H., Hoeijmakers J.H.J., Myung K.;
RT "Polyubiquitination of proliferating cell nuclear antigen by HLTF and
RT SHPRH prevents genomic instability from stalled replication forks.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:12411-12416(2008).
RN [12]
RP REVIEW, AND FUNCTION.
RX PubMed=19754430; DOI=10.1042/BST0370937;
RA Komander D.;
RT "The emerging complexity of protein ubiquitination.";
RL Biochem. Soc. Trans. 37:937-953(2009).
RN [13]
RP CLEAVAGE BY UCHL3 (VARIANT UBB(+1)).
RX PubMed=21762696; DOI=10.1016/j.febslet.2011.06.037;
RA Dennissen F.J., Kholod N., Hermes D.J., Kemmerling N.,
RA Steinbusch H.W., Dantuma N.P., van Leeuwen F.W.;
RT "Mutant ubiquitin (UBB(+1)) associated with neurodegenerative
RT disorders is hydrolyzed by ubiquitin C-terminal hydrolase L3 (UCH-
RT L3).";
RL FEBS Lett. 585:2568-2574(2011).
RN [14]
RP IDENTIFICATION OF VARIANT UBB(+1).
RX PubMed=9422699; DOI=10.1126/science.279.5348.242;
RA van Leeuwen F.W., de Kleijn D.P., van den Hurk H.H., Neubauer A.,
RA Sonnemans M.A., Sluijs J.A., Koycu S., Ramdjielal R.D., Salehi A.,
RA Martens G.J., Grosveld F.G., Peter J., Burbach H., Hol E.M.;
RT "Frameshift mutants of beta amyloid precursor protein and ubiquitin-B
RT in Alzheimer's and Down patients.";
RL Science 279:242-247(1998).
RN [15]
RP TISSUE SPECIFICITY (VARIANT UBB(+1)).
RX PubMed=14597671; DOI=10.1096/fj.03-0205com;
RA Fischer D.F., De Vos R.A., Van Dijk R., De Vrij F.M., Proper E.A.,
RA Sonnemans M.A., Verhage M.C., Sluijs J.A., Hobo B., Zouambia M.,
RA Steur E.N., Kamphorst W., Hol E.M., Van Leeuwen F.W.;
RT "Disease-specific accumulation of mutant ubiquitin as a marker for
RT proteasomal dysfunction in the brain.";
RL FASEB J. 17:2014-2024(2003).
CC -!- FUNCTION: Ubiquitin exists either covalently attached to another
CC protein, or free (unanchored). When covalently bound, it is
CC conjugated to target proteins via an isopeptide bond either as a
CC monomer (monoubiquitin), a polymer linked via different Lys
CC residues of the ubiquitin (polyubiquitin chains) or a linear
CC polymer linked via the initiator Met of the ubiquitin (linear
CC polyubiquitin chains). Polyubiquitin chains, when attached to a
CC target protein, have different functions depending on the Lys
CC residue of the ubiquitin that is linked: Lys-6-linked may be
CC involved in DNA repair; Lys-11-linked is involved in ERAD
CC (endoplasmic reticulum-associated degradation) and in cell-cycle
CC regulation; Lys-29-linked is involved in lysosomal degradation;
CC Lys-33-linked is involved in kinase modification; Lys-48-linked is
CC involved in protein degradation via the proteasome; Lys-63-linked
CC is involved in endocytosis, DNA-damage responses as well as in
CC signaling processes leading to activation of the transcription
CC factor NF-kappa-B. Linear polymer chains formed via attachment by
CC the initiator Met lead to cell signaling. Ubiquitin is usually
CC conjugated to Lys residues of target proteins, however, in rare
CC cases, conjugation to Cys or Ser residues has been observed. When
CC polyubiquitin is free (unanchored-polyubiquitin), it also has
CC distinct roles, such as in activation of protein kinases, and in
CC signaling.
CC -!- INTERACTION:
CC Q8IVM0:CCDC50; NbExp=2; IntAct=EBI-413034, EBI-723996;
CC P28562:DUSP1; NbExp=2; IntAct=EBI-413034, EBI-975493;
CC Q9UJY5:GGA1; NbExp=3; IntAct=EBI-413034, EBI-447141;
CC Q9NZ52:GGA3; NbExp=2; IntAct=EBI-413034, EBI-447404;
CC Q60592:Mast2 (xeno); NbExp=2; IntAct=EBI-413034, EBI-493888;
CC P33993:MCM7; NbExp=2; IntAct=EBI-413034, EBI-355924;
CC Q9DLK6:NP (xeno); NbExp=2; IntAct=EBI-413034, EBI-8433218;
CC P24610:Pax3 (xeno); NbExp=2; IntAct=EBI-413034, EBI-1208116;
CC Q9UJ41:RABGEF1; NbExp=6; IntAct=EBI-413034, EBI-913954;
CC Q9Y3C5:RNF11; NbExp=2; IntAct=EBI-413034, EBI-396669;
CC Q68DV7:RNF43; NbExp=2; IntAct=EBI-413034, EBI-1647060;
CC Q9HAU4:SMURF2; NbExp=4; IntAct=EBI-413034, EBI-396727;
CC -!- SUBCELLULAR LOCATION: Ubiquitin: Cytoplasm (By similarity).
CC Nucleus (By similarity).
CC -!- MISCELLANEOUS: Ubiquitin is encoded by 4 different genes. UBA52
CC and RPS27A genes code for a single copy of ubiquitin fused to the
CC ribosomal proteins L40 and S27a, respectively. UBB and UBC genes
CC code for a polyubiquitin precursor with exact head to tail
CC repeats, the number of repeats differ between species and strains.
CC -!- MISCELLANEOUS: The mRNA encoding variant UBB(+1) is produced by an
CC unknown mechanism involving the deletion of a GT dinucleotide in
CC the close proximity of a GAGAG motif (PubMed:9422699). This
CC variant mRNA is found in normal brain, but the encoded protein
CC accumulates only in brain neurofibrillary tangles and neuritic
CC plaques in Alzheimer disease and other tauopathies, as well as
CC polyglutaminopathies (PubMed:14597671). UBB(+1) variant cannot be
CC used for polyubiquitination, is not effectively degraded by the
CC proteasome when ubiquitinated and ubiquitinated UBB(+1) is
CC refractory to disassembly by deubiquitinating enzymes (DUBs). In
CC healthy brain, UBB(+1) C-terminus can be cleaved by UCHL3
CC (PubMed:21762696).
CC -!- MISCELLANEOUS: For a better understanding, features related to
CC ubiquitin are only indicated for the first chain.
CC -!- SIMILARITY: Belongs to the ubiquitin family.
CC -!- SIMILARITY: Contains 3 ubiquitin-like domains.
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DR EMBL; X04803; CAA28495.1; -; Genomic_DNA.
DR EMBL; AB089617; BAC56955.1; -; Genomic_DNA.
DR EMBL; AC093484; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC000379; AAH00379.1; -; mRNA.
DR EMBL; BC009301; AAH09301.1; -; mRNA.
DR EMBL; BC015127; AAH15127.1; -; mRNA.
DR EMBL; BC026301; AAH26301.1; -; mRNA.
DR EMBL; BC031027; AAH31027.1; -; mRNA.
DR EMBL; BC046123; AAH46123.1; -; mRNA.
DR PIR; A26437; UQHUB.
DR RefSeq; NP_001268645.1; NM_001281716.1.
DR RefSeq; NP_001268646.1; NM_001281717.1.
DR RefSeq; NP_001268647.1; NM_001281718.1.
DR RefSeq; NP_001268648.1; NM_001281719.1.
DR RefSeq; NP_001268649.1; NM_001281720.1.
DR RefSeq; NP_061828.1; NM_018955.3.
DR UniGene; Hs.356190; -.
DR UniGene; Hs.741549; -.
DR ProteinModelPortal; P0CG47; -.
DR SMR; P0CG47; 1-227.
DR IntAct; P0CG47; 66.
DR MINT; MINT-8084593; -.
DR PhosphoSite; P0CG47; -.
DR DMDM; 302595875; -.
DR PRIDE; P0CG47; -.
DR DNASU; 7314; -.
DR Ensembl; ENST00000302182; ENSP00000304697; ENSG00000170315.
DR Ensembl; ENST00000395837; ENSP00000379178; ENSG00000170315.
DR Ensembl; ENST00000395839; ENSP00000379180; ENSG00000170315.
DR GeneID; 7314; -.
DR KEGG; hsa:7314; -.
DR UCSC; uc002gpx.3; human.
DR CTD; 7314; -.
DR GeneCards; GC17P016301; -.
DR HGNC; HGNC:12463; UBB.
DR HPA; CAB013048; -.
DR HPA; HPA041344; -.
DR HPA; HPA049132; -.
DR MIM; 191339; gene.
DR neXtProt; NX_P0CG47; -.
DR KO; K04551; -.
DR OMA; YTVRPGE; -.
DR PhylomeDB; P0CG47; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_11123; Membrane Trafficking.
DR Reactome; REACT_115202; Signal Transduction.
DR Reactome; REACT_115566; Cell Cycle.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_118324; Disease.
DR Reactome; REACT_118381; Disease.
DR Reactome; REACT_120956; Cellular responses to stress.
DR Reactome; REACT_13487; Ubiquitination of PAK-2p34.
DR Reactome; REACT_13505; Proteasome mediated degradation of PAK-2p34.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR Reactome; REACT_2001; Receptor-ligand binding initiates the second proteolytic cleavage of Notch receptor.
DR Reactome; REACT_21257; Metabolism of RNA.
DR Reactome; REACT_21300; Mitotic M-M/G1 phases.
DR Reactome; REACT_216; DNA Repair.
DR Reactome; REACT_24941; Circadian Clock.
DR Reactome; REACT_383; DNA Replication.
DR Reactome; REACT_578; Apoptosis.
DR Reactome; REACT_6782; TRAF6 Mediated Induction of proinflammatory cytokines.
DR Reactome; REACT_6850; Cdc20:Phospho-APC/C mediated degradation of Cyclin A.
DR Reactome; REACT_6900; Immune System.
DR Reactome; REACT_71; Gene Expression.
DR Reactome; REACT_8017; APC-Cdc20 mediated degradation of Nek2A.
DR Reactome; REACT_81380; Receptor-ligand binding initiates the second proteolytic cleavage of Notch receptor.
DR Reactome; REACT_97910; Signal Transduction.
DR ChiTaRS; UBB; human.
DR GeneWiki; Ubiquitin_B; -.
DR GenomeRNAi; 7314; -.
DR NextBio; 28592; -.
DR PRO; PR:P0CG47; -.
DR ArrayExpress; P0CG47; -.
DR Bgee; P0CG47; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0030666; C:endocytic vesicle membrane; TAS:Reactome.
DR GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0000187; P:activation of MAPK activity; TAS:Reactome.
DR GO; GO:0031145; P:anaphase-promoting complex-dependent proteasomal ubiquitin-dependent protein catabolic process; TAS:Reactome.
DR GO; GO:0002479; P:antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent; TAS:Reactome.
DR GO; GO:0097190; P:apoptotic signaling pathway; TAS:Reactome.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0006977; P:DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; TAS:Reactome.
DR GO; GO:0006281; P:DNA repair; TAS:Reactome.
DR GO; GO:0016197; P:endosomal transport; TAS:Reactome.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; TAS:Reactome.
DR GO; GO:0007249; P:I-kappaB kinase/NF-kappaB cascade; TAS:Reactome.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0034220; P:ion transmembrane transport; TAS:Reactome.
DR GO; GO:0007254; P:JNK cascade; TAS:Reactome.
DR GO; GO:0016071; P:mRNA metabolic process; TAS:Reactome.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0043066; P:negative regulation of apoptotic process; TAS:Reactome.
DR GO; GO:0042059; P:negative regulation of epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; TAS:Reactome.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; TAS:Reactome.
DR GO; GO:0032480; P:negative regulation of type I interferon production; TAS:Reactome.
DR GO; GO:0051436; P:negative regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle; TAS:Reactome.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0007220; P:Notch receptor processing; TAS:Reactome.
DR GO; GO:0007219; P:Notch signaling pathway; TAS:Reactome.
DR GO; GO:0070423; P:nucleotide-binding oligomerization domain containing signaling pathway; TAS:Reactome.
DR GO; GO:0043065; P:positive regulation of apoptotic process; TAS:Reactome.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; TAS:Reactome.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; TAS:Reactome.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; TAS:Reactome.
DR GO; GO:0032481; P:positive regulation of type I interferon production; TAS:Reactome.
DR GO; GO:0051437; P:positive regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle; TAS:Reactome.
DR GO; GO:0000209; P:protein polyubiquitination; TAS:Reactome.
DR GO; GO:0061418; P:regulation of transcription from RNA polymerase II promoter in response to hypoxia; TAS:Reactome.
DR GO; GO:0050852; P:T cell receptor signaling pathway; TAS:Reactome.
DR GO; GO:0034166; P:toll-like receptor 10 signaling pathway; TAS:Reactome.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0034146; P:toll-like receptor 5 signaling pathway; TAS:Reactome.
DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
DR GO; GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0006367; P:transcription initiation from RNA polymerase II promoter; TAS:Reactome.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; TAS:Reactome.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0019082; P:viral protein processing; TAS:Reactome.
DR GO; GO:0019068; P:virion assembly; TAS:Reactome.
DR InterPro; IPR019956; Ubiquitin.
DR InterPro; IPR019954; Ubiquitin_CS.
DR InterPro; IPR000626; Ubiquitin_dom.
DR Pfam; PF00240; ubiquitin; 3.
DR PRINTS; PR00348; UBIQUITIN.
DR SMART; SM00213; UBQ; 3.
DR PROSITE; PS00299; UBIQUITIN_1; 3.
DR PROSITE; PS50053; UBIQUITIN_2; 3.
PE 1: Evidence at protein level;
KW Complete proteome; Cytoplasm; Direct protein sequencing;
KW Isopeptide bond; Nucleus; Reference proteome; Repeat; Ubl conjugation.
FT CHAIN 1 76 Ubiquitin.
FT /FTId=PRO_0000396174.
FT CHAIN 77 152 Ubiquitin.
FT /FTId=PRO_0000396175.
FT CHAIN 153 228 Ubiquitin.
FT /FTId=PRO_0000396176.
FT PROPEP 229 229
FT /FTId=PRO_0000396177.
FT DOMAIN 1 76 Ubiquitin-like 1.
FT DOMAIN 77 152 Ubiquitin-like 2.
FT DOMAIN 153 228 Ubiquitin-like 3.
FT BINDING 54 54 Activating enzyme.
FT BINDING 72 72 Activating enzyme.
FT SITE 68 68 Essential for function.
FT CROSSLNK 6 6 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT CROSSLNK 11 11 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT CROSSLNK 27 27 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin)
FT (Probable).
FT CROSSLNK 29 29 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT CROSSLNK 33 33 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin) (By
FT similarity).
FT CROSSLNK 48 48 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT CROSSLNK 63 63 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT CROSSLNK 76 76 Glycyl lysine isopeptide (Gly-Lys)
FT (interchain with K-? in acceptor
FT proteins).
FT VARIANT 76 229 GMQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQ
FT QRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGGMQIFV
FT KTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIFA
FT GKQLEDGRTLSDYNIQKESTLHLVLRLRGGC -> YADLRE
FT DPDRQDHHPGSGAQ (in UBB(+1); loss of
FT polyubiquitination; impairs the
FT ubiquitin-proteasome pathway; refractory
FT to disassembly by DUBs; slow degradation
FT by UCHL3).
FT /FTId=VAR_066248.
FT MUTAGEN 48 48 K->R: No effect on HLTF-mediated
FT polyubiquitination of PCNA.
FT MUTAGEN 63 63 K->R: Abolishes HLTF-mediated
FT polyubiquitination of PCNA.
SQ SEQUENCE 229 AA; 25762 MW; 33011162F1C48BB1 CRC64;
MQIFVKTLTG KTITLEVEPS DTIENVKAKI QDKEGIPPDQ QRLIFAGKQL EDGRTLSDYN
IQKESTLHLV LRLRGGMQIF VKTLTGKTIT LEVEPSDTIE NVKAKIQDKE GIPPDQQRLI
FAGKQLEDGR TLSDYNIQKE STLHLVLRLR GGMQIFVKTL TGKTITLEVE PSDTIENVKA
KIQDKEGIPP DQQRLIFAGK QLEDGRTLSD YNIQKESTLH LVLRLRGGC
//
ID UBB_HUMAN Reviewed; 229 AA.
AC P0CG47; P02248; P02249; P02250; P62988; Q29120; Q6LBL4; Q6LDU5;
read moreAC Q8WYN8; Q91887; Q91888; Q9BWD6; Q9BX98; Q9UEF2; Q9UEG1; Q9UEK8;
AC Q9UPK7;
DT 10-AUG-2010, integrated into UniProtKB/Swiss-Prot.
DT 10-AUG-2010, sequence version 1.
DT 22-JAN-2014, entry version 38.
DE RecName: Full=Polyubiquitin-B;
DE Contains:
DE RecName: Full=Ubiquitin;
DE Flags: Precursor;
GN Name=UBB;
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 [GENOMIC DNA].
RC TISSUE=Blood;
RX PubMed=3029682; DOI=10.1093/nar/15.2.443;
RA Baker R.T., Board P.G.;
RT "The human ubiquitin gene family: structure of a gene and pseudogenes
RT from the Ub B subfamily.";
RL Nucleic Acids Res. 15:443-463(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=14745543; DOI=10.1007/s00239-003-2532-4;
RA Tachikui H., Saitou N., Nakajima T., Hayasaka I., Ishida T., Inoue I.;
RT "Lineage-specific homogenization of the polyubiquitin gene among human
RT and great apes.";
RL J. Mol. Evol. 57:737-744(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R.,
RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N.,
RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B.,
RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J.,
RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E.,
RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J.,
RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C.,
RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in
RT the human lineage.";
RL Nature 440:1045-1049(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, Liver, and Lung;
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 [5]
RP PROTEIN SEQUENCE OF 1-27; 30-42 AND 55-72, AND MASS SPECTROMETRY.
RC TISSUE=Fetal brain cortex;
RA Lubec G., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [6]
RP PROTEIN SEQUENCE OF 1-74.
RX PubMed=124018; DOI=10.1038/255423a0;
RA Schlesinger D.H., Goldstein G.;
RT "Hybrid troponin reconstituted from vertebrate and arthropod
RT subunits.";
RL Nature 255:423-424(1975).
RN [7]
RP PROTEIN SEQUENCE OF 1-27 AND 43-54, UBIQUITINATION AT LYS-6; LYS-11
RP AND LYS-48, AND MASS SPECTROMETRY.
RX PubMed=16443603; DOI=10.1074/jbc.M512786200;
RA Cripps D., Thomas S.N., Jeng Y., Yang F., Davies P., Yang A.J.;
RT "Alzheimer disease-specific conformation of hyperphosphorylated paired
RT helical filament-tau is polyubiquitinated through Lys-48, Lys-11, and
RT Lys-6 ubiquitin conjugation.";
RL J. Biol. Chem. 281:10825-10838(2006).
RN [8]
RP FUNCTION, UBIQUITINATION AT LYS-11; LYS-29; LYS-48 AND LYS-63, AND
RP MASS SPECTROMETRY.
RX PubMed=16543144; DOI=10.1016/j.molcel.2006.02.018;
RA Huang F., Kirkpatrick D., Jiang X., Gygi S.P., Sorkin A.;
RT "Differential regulation of EGF receptor internalization and
RT degradation by multiubiquitination within the kinase domain.";
RL Mol. Cell 21:737-748(2006).
RN [9]
RP UBIQUITINATION AT LYS-27.
RX PubMed=15466860; DOI=10.1074/jbc.M402916200;
RA Okumura F., Hatakeyama S., Matsumoto M., Kamura T., Nakayama K.;
RT "Functional regulation of FEZ1 by the U-box-type ubiquitin ligase E4B
RT contributes to neuritogenesis.";
RL J. Biol. Chem. 279:53533-53543(2004).
RN [10]
RP UBIQUITINATION [LARGE SCALE ANALYSIS] AT LYS-48, AND MASS
RP SPECTROMETRY.
RC TISSUE=Lung adenocarcinoma;
RX PubMed=17203973; DOI=10.1021/pr060438j;
RA Vasilescu J., Zweitzig D.R., Denis N.J., Smith J.C., Ethier M.,
RA Haines D.S., Figeys D.;
RT "The proteomic reactor facilitates the analysis of affinity-purified
RT proteins by mass spectrometry: application for identifying
RT ubiquitinated proteins in human cells.";
RL J. Proteome Res. 6:298-305(2007).
RN [11]
RP UBIQUITINATION AT LYS-63, AND MUTAGENESIS OF LYS-48 AND LYS-63.
RX PubMed=18719106; DOI=10.1073/pnas.0805685105;
RA Motegi A., Liaw H.-J., Lee K.-Y., Roest H.P., Maas A., Wu X.,
RA Moinova H., Markowitz S.D., Ding H., Hoeijmakers J.H.J., Myung K.;
RT "Polyubiquitination of proliferating cell nuclear antigen by HLTF and
RT SHPRH prevents genomic instability from stalled replication forks.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:12411-12416(2008).
RN [12]
RP REVIEW, AND FUNCTION.
RX PubMed=19754430; DOI=10.1042/BST0370937;
RA Komander D.;
RT "The emerging complexity of protein ubiquitination.";
RL Biochem. Soc. Trans. 37:937-953(2009).
RN [13]
RP CLEAVAGE BY UCHL3 (VARIANT UBB(+1)).
RX PubMed=21762696; DOI=10.1016/j.febslet.2011.06.037;
RA Dennissen F.J., Kholod N., Hermes D.J., Kemmerling N.,
RA Steinbusch H.W., Dantuma N.P., van Leeuwen F.W.;
RT "Mutant ubiquitin (UBB(+1)) associated with neurodegenerative
RT disorders is hydrolyzed by ubiquitin C-terminal hydrolase L3 (UCH-
RT L3).";
RL FEBS Lett. 585:2568-2574(2011).
RN [14]
RP IDENTIFICATION OF VARIANT UBB(+1).
RX PubMed=9422699; DOI=10.1126/science.279.5348.242;
RA van Leeuwen F.W., de Kleijn D.P., van den Hurk H.H., Neubauer A.,
RA Sonnemans M.A., Sluijs J.A., Koycu S., Ramdjielal R.D., Salehi A.,
RA Martens G.J., Grosveld F.G., Peter J., Burbach H., Hol E.M.;
RT "Frameshift mutants of beta amyloid precursor protein and ubiquitin-B
RT in Alzheimer's and Down patients.";
RL Science 279:242-247(1998).
RN [15]
RP TISSUE SPECIFICITY (VARIANT UBB(+1)).
RX PubMed=14597671; DOI=10.1096/fj.03-0205com;
RA Fischer D.F., De Vos R.A., Van Dijk R., De Vrij F.M., Proper E.A.,
RA Sonnemans M.A., Verhage M.C., Sluijs J.A., Hobo B., Zouambia M.,
RA Steur E.N., Kamphorst W., Hol E.M., Van Leeuwen F.W.;
RT "Disease-specific accumulation of mutant ubiquitin as a marker for
RT proteasomal dysfunction in the brain.";
RL FASEB J. 17:2014-2024(2003).
CC -!- FUNCTION: Ubiquitin exists either covalently attached to another
CC protein, or free (unanchored). When covalently bound, it is
CC conjugated to target proteins via an isopeptide bond either as a
CC monomer (monoubiquitin), a polymer linked via different Lys
CC residues of the ubiquitin (polyubiquitin chains) or a linear
CC polymer linked via the initiator Met of the ubiquitin (linear
CC polyubiquitin chains). Polyubiquitin chains, when attached to a
CC target protein, have different functions depending on the Lys
CC residue of the ubiquitin that is linked: Lys-6-linked may be
CC involved in DNA repair; Lys-11-linked is involved in ERAD
CC (endoplasmic reticulum-associated degradation) and in cell-cycle
CC regulation; Lys-29-linked is involved in lysosomal degradation;
CC Lys-33-linked is involved in kinase modification; Lys-48-linked is
CC involved in protein degradation via the proteasome; Lys-63-linked
CC is involved in endocytosis, DNA-damage responses as well as in
CC signaling processes leading to activation of the transcription
CC factor NF-kappa-B. Linear polymer chains formed via attachment by
CC the initiator Met lead to cell signaling. Ubiquitin is usually
CC conjugated to Lys residues of target proteins, however, in rare
CC cases, conjugation to Cys or Ser residues has been observed. When
CC polyubiquitin is free (unanchored-polyubiquitin), it also has
CC distinct roles, such as in activation of protein kinases, and in
CC signaling.
CC -!- INTERACTION:
CC Q8IVM0:CCDC50; NbExp=2; IntAct=EBI-413034, EBI-723996;
CC P28562:DUSP1; NbExp=2; IntAct=EBI-413034, EBI-975493;
CC Q9UJY5:GGA1; NbExp=3; IntAct=EBI-413034, EBI-447141;
CC Q9NZ52:GGA3; NbExp=2; IntAct=EBI-413034, EBI-447404;
CC Q60592:Mast2 (xeno); NbExp=2; IntAct=EBI-413034, EBI-493888;
CC P33993:MCM7; NbExp=2; IntAct=EBI-413034, EBI-355924;
CC Q9DLK6:NP (xeno); NbExp=2; IntAct=EBI-413034, EBI-8433218;
CC P24610:Pax3 (xeno); NbExp=2; IntAct=EBI-413034, EBI-1208116;
CC Q9UJ41:RABGEF1; NbExp=6; IntAct=EBI-413034, EBI-913954;
CC Q9Y3C5:RNF11; NbExp=2; IntAct=EBI-413034, EBI-396669;
CC Q68DV7:RNF43; NbExp=2; IntAct=EBI-413034, EBI-1647060;
CC Q9HAU4:SMURF2; NbExp=4; IntAct=EBI-413034, EBI-396727;
CC -!- SUBCELLULAR LOCATION: Ubiquitin: Cytoplasm (By similarity).
CC Nucleus (By similarity).
CC -!- MISCELLANEOUS: Ubiquitin is encoded by 4 different genes. UBA52
CC and RPS27A genes code for a single copy of ubiquitin fused to the
CC ribosomal proteins L40 and S27a, respectively. UBB and UBC genes
CC code for a polyubiquitin precursor with exact head to tail
CC repeats, the number of repeats differ between species and strains.
CC -!- MISCELLANEOUS: The mRNA encoding variant UBB(+1) is produced by an
CC unknown mechanism involving the deletion of a GT dinucleotide in
CC the close proximity of a GAGAG motif (PubMed:9422699). This
CC variant mRNA is found in normal brain, but the encoded protein
CC accumulates only in brain neurofibrillary tangles and neuritic
CC plaques in Alzheimer disease and other tauopathies, as well as
CC polyglutaminopathies (PubMed:14597671). UBB(+1) variant cannot be
CC used for polyubiquitination, is not effectively degraded by the
CC proteasome when ubiquitinated and ubiquitinated UBB(+1) is
CC refractory to disassembly by deubiquitinating enzymes (DUBs). In
CC healthy brain, UBB(+1) C-terminus can be cleaved by UCHL3
CC (PubMed:21762696).
CC -!- MISCELLANEOUS: For a better understanding, features related to
CC ubiquitin are only indicated for the first chain.
CC -!- SIMILARITY: Belongs to the ubiquitin family.
CC -!- SIMILARITY: Contains 3 ubiquitin-like domains.
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DR EMBL; X04803; CAA28495.1; -; Genomic_DNA.
DR EMBL; AB089617; BAC56955.1; -; Genomic_DNA.
DR EMBL; AC093484; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC000379; AAH00379.1; -; mRNA.
DR EMBL; BC009301; AAH09301.1; -; mRNA.
DR EMBL; BC015127; AAH15127.1; -; mRNA.
DR EMBL; BC026301; AAH26301.1; -; mRNA.
DR EMBL; BC031027; AAH31027.1; -; mRNA.
DR EMBL; BC046123; AAH46123.1; -; mRNA.
DR PIR; A26437; UQHUB.
DR RefSeq; NP_001268645.1; NM_001281716.1.
DR RefSeq; NP_001268646.1; NM_001281717.1.
DR RefSeq; NP_001268647.1; NM_001281718.1.
DR RefSeq; NP_001268648.1; NM_001281719.1.
DR RefSeq; NP_001268649.1; NM_001281720.1.
DR RefSeq; NP_061828.1; NM_018955.3.
DR UniGene; Hs.356190; -.
DR UniGene; Hs.741549; -.
DR ProteinModelPortal; P0CG47; -.
DR SMR; P0CG47; 1-227.
DR IntAct; P0CG47; 66.
DR MINT; MINT-8084593; -.
DR PhosphoSite; P0CG47; -.
DR DMDM; 302595875; -.
DR PRIDE; P0CG47; -.
DR DNASU; 7314; -.
DR Ensembl; ENST00000302182; ENSP00000304697; ENSG00000170315.
DR Ensembl; ENST00000395837; ENSP00000379178; ENSG00000170315.
DR Ensembl; ENST00000395839; ENSP00000379180; ENSG00000170315.
DR GeneID; 7314; -.
DR KEGG; hsa:7314; -.
DR UCSC; uc002gpx.3; human.
DR CTD; 7314; -.
DR GeneCards; GC17P016301; -.
DR HGNC; HGNC:12463; UBB.
DR HPA; CAB013048; -.
DR HPA; HPA041344; -.
DR HPA; HPA049132; -.
DR MIM; 191339; gene.
DR neXtProt; NX_P0CG47; -.
DR KO; K04551; -.
DR OMA; YTVRPGE; -.
DR PhylomeDB; P0CG47; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_11123; Membrane Trafficking.
DR Reactome; REACT_115202; Signal Transduction.
DR Reactome; REACT_115566; Cell Cycle.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_118324; Disease.
DR Reactome; REACT_118381; Disease.
DR Reactome; REACT_120956; Cellular responses to stress.
DR Reactome; REACT_13487; Ubiquitination of PAK-2p34.
DR Reactome; REACT_13505; Proteasome mediated degradation of PAK-2p34.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR Reactome; REACT_2001; Receptor-ligand binding initiates the second proteolytic cleavage of Notch receptor.
DR Reactome; REACT_21257; Metabolism of RNA.
DR Reactome; REACT_21300; Mitotic M-M/G1 phases.
DR Reactome; REACT_216; DNA Repair.
DR Reactome; REACT_24941; Circadian Clock.
DR Reactome; REACT_383; DNA Replication.
DR Reactome; REACT_578; Apoptosis.
DR Reactome; REACT_6782; TRAF6 Mediated Induction of proinflammatory cytokines.
DR Reactome; REACT_6850; Cdc20:Phospho-APC/C mediated degradation of Cyclin A.
DR Reactome; REACT_6900; Immune System.
DR Reactome; REACT_71; Gene Expression.
DR Reactome; REACT_8017; APC-Cdc20 mediated degradation of Nek2A.
DR Reactome; REACT_81380; Receptor-ligand binding initiates the second proteolytic cleavage of Notch receptor.
DR Reactome; REACT_97910; Signal Transduction.
DR ChiTaRS; UBB; human.
DR GeneWiki; Ubiquitin_B; -.
DR GenomeRNAi; 7314; -.
DR NextBio; 28592; -.
DR PRO; PR:P0CG47; -.
DR ArrayExpress; P0CG47; -.
DR Bgee; P0CG47; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0030666; C:endocytic vesicle membrane; TAS:Reactome.
DR GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0000187; P:activation of MAPK activity; TAS:Reactome.
DR GO; GO:0031145; P:anaphase-promoting complex-dependent proteasomal ubiquitin-dependent protein catabolic process; TAS:Reactome.
DR GO; GO:0002479; P:antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent; TAS:Reactome.
DR GO; GO:0097190; P:apoptotic signaling pathway; TAS:Reactome.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0006977; P:DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; TAS:Reactome.
DR GO; GO:0006281; P:DNA repair; TAS:Reactome.
DR GO; GO:0016197; P:endosomal transport; TAS:Reactome.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; TAS:Reactome.
DR GO; GO:0007249; P:I-kappaB kinase/NF-kappaB cascade; TAS:Reactome.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0034220; P:ion transmembrane transport; TAS:Reactome.
DR GO; GO:0007254; P:JNK cascade; TAS:Reactome.
DR GO; GO:0016071; P:mRNA metabolic process; TAS:Reactome.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0043066; P:negative regulation of apoptotic process; TAS:Reactome.
DR GO; GO:0042059; P:negative regulation of epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; TAS:Reactome.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; TAS:Reactome.
DR GO; GO:0032480; P:negative regulation of type I interferon production; TAS:Reactome.
DR GO; GO:0051436; P:negative regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle; TAS:Reactome.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0007220; P:Notch receptor processing; TAS:Reactome.
DR GO; GO:0007219; P:Notch signaling pathway; TAS:Reactome.
DR GO; GO:0070423; P:nucleotide-binding oligomerization domain containing signaling pathway; TAS:Reactome.
DR GO; GO:0043065; P:positive regulation of apoptotic process; TAS:Reactome.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; TAS:Reactome.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; TAS:Reactome.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; TAS:Reactome.
DR GO; GO:0032481; P:positive regulation of type I interferon production; TAS:Reactome.
DR GO; GO:0051437; P:positive regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle; TAS:Reactome.
DR GO; GO:0000209; P:protein polyubiquitination; TAS:Reactome.
DR GO; GO:0061418; P:regulation of transcription from RNA polymerase II promoter in response to hypoxia; TAS:Reactome.
DR GO; GO:0050852; P:T cell receptor signaling pathway; TAS:Reactome.
DR GO; GO:0034166; P:toll-like receptor 10 signaling pathway; TAS:Reactome.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0034146; P:toll-like receptor 5 signaling pathway; TAS:Reactome.
DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
DR GO; GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0006367; P:transcription initiation from RNA polymerase II promoter; TAS:Reactome.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; TAS:Reactome.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0019082; P:viral protein processing; TAS:Reactome.
DR GO; GO:0019068; P:virion assembly; TAS:Reactome.
DR InterPro; IPR019956; Ubiquitin.
DR InterPro; IPR019954; Ubiquitin_CS.
DR InterPro; IPR000626; Ubiquitin_dom.
DR Pfam; PF00240; ubiquitin; 3.
DR PRINTS; PR00348; UBIQUITIN.
DR SMART; SM00213; UBQ; 3.
DR PROSITE; PS00299; UBIQUITIN_1; 3.
DR PROSITE; PS50053; UBIQUITIN_2; 3.
PE 1: Evidence at protein level;
KW Complete proteome; Cytoplasm; Direct protein sequencing;
KW Isopeptide bond; Nucleus; Reference proteome; Repeat; Ubl conjugation.
FT CHAIN 1 76 Ubiquitin.
FT /FTId=PRO_0000396174.
FT CHAIN 77 152 Ubiquitin.
FT /FTId=PRO_0000396175.
FT CHAIN 153 228 Ubiquitin.
FT /FTId=PRO_0000396176.
FT PROPEP 229 229
FT /FTId=PRO_0000396177.
FT DOMAIN 1 76 Ubiquitin-like 1.
FT DOMAIN 77 152 Ubiquitin-like 2.
FT DOMAIN 153 228 Ubiquitin-like 3.
FT BINDING 54 54 Activating enzyme.
FT BINDING 72 72 Activating enzyme.
FT SITE 68 68 Essential for function.
FT CROSSLNK 6 6 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT CROSSLNK 11 11 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT CROSSLNK 27 27 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin)
FT (Probable).
FT CROSSLNK 29 29 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT CROSSLNK 33 33 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin) (By
FT similarity).
FT CROSSLNK 48 48 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT CROSSLNK 63 63 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT CROSSLNK 76 76 Glycyl lysine isopeptide (Gly-Lys)
FT (interchain with K-? in acceptor
FT proteins).
FT VARIANT 76 229 GMQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQ
FT QRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGGMQIFV
FT KTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIFA
FT GKQLEDGRTLSDYNIQKESTLHLVLRLRGGC -> YADLRE
FT DPDRQDHHPGSGAQ (in UBB(+1); loss of
FT polyubiquitination; impairs the
FT ubiquitin-proteasome pathway; refractory
FT to disassembly by DUBs; slow degradation
FT by UCHL3).
FT /FTId=VAR_066248.
FT MUTAGEN 48 48 K->R: No effect on HLTF-mediated
FT polyubiquitination of PCNA.
FT MUTAGEN 63 63 K->R: Abolishes HLTF-mediated
FT polyubiquitination of PCNA.
SQ SEQUENCE 229 AA; 25762 MW; 33011162F1C48BB1 CRC64;
MQIFVKTLTG KTITLEVEPS DTIENVKAKI QDKEGIPPDQ QRLIFAGKQL EDGRTLSDYN
IQKESTLHLV LRLRGGMQIF VKTLTGKTIT LEVEPSDTIE NVKAKIQDKE GIPPDQQRLI
FAGKQLEDGR TLSDYNIQKE STLHLVLRLR GGMQIFVKTL TGKTITLEVE PSDTIENVKA
KIQDKEGIPP DQQRLIFAGK QLEDGRTLSD YNIQKESTLH LVLRLRGGC
//
MIM
191339
*RECORD*
*FIELD* NO
191339
*FIELD* TI
*191339 UBIQUITIN B; UBB
;;POLYUBIQUITIN B
*FIELD* TX
DESCRIPTION
Ubiquitin, a small protein consisting of 76 amino acids, has been found
read morein all eukaryotic cells studied. It is one of the most conserved
proteins known; the amino acid sequence is identical from insects to
humans, and there are only 3 substitutions within the plant and yeast
sequences. Two classes of ubiquitin genes are recognized. Class I is a
polyubiquitin gene, such as UBB or UBC (191340), encoding a polyprotein
of tandemly repeated ubiquitins. The class II genes are fusion products
between a single ubiquitin gene and 1 of 2 other possible sequences,
either 52 or 76 to 80 predominantly basic amino acids (see UBA52,
191321, and UBA80, 191343, respectively). Ubiquitin is required for
ATP-dependent, nonlysosomal intracellular protein degradation, which
eliminates most intracellular defective problems as well as normal
proteins with a rapid turnover. Degradation involves covalent binding of
ubiquitin to the protein to be degraded, through isopeptide bonds from
the C-terminal glycine residue to the epsilon-amino groups of lysyl side
chains. Presumably, the function of ubiquitin is to label the protein
for disposal by intracellular proteases. The most abundant
ubiquitin-protein conjugate, however, is ubiquitin-H2A, in which
ubiquitin is bound to lys119 in histone H2A; this conjugate is not
degraded. Since such ubiquitinated histones are present primarily in
actively transcribed chromosomal regions, ubiquitin may play a role in
regulation of gene expression (summary by Wiborg et al. (1985) and Baker
and Board (1987)).
CLONING
Wiborg et al. (1985) determined that ubiquitin is encoded as a multigene
family.
Baker and Board (1987) studied cDNA and genomic clones of ubiquitin.
MAPPING
By in situ hybridization, Webb et al. (1990) assigned the 3-coding unit
polyubiquitin gene UBB and its nonprocessed pseudogene to chromosome
17p12-p11.1.
GENE FUNCTION
Finley et al. (1989) demonstrated that the basic amino acids fused to
ubiquitin in the class II gene products represent ribosomal proteins,
and that their fusion to ubiquitin performs a crucial role in ribosome
biogenesis in the Saccharomyces cerevisiae. Redman and Rechsteiner
(1989) studied these 3-prime in-frame extensions of the ubiquitin genes
in mammalian systems and concluded, as did Finley et al. (1989), that
the C-terminal extension proteins are ribosomal components.
Sutovsky et al. (1999) demonstrated that sperm mitochondria are
selectively marked for destruction by a ubiquitin tag. In fertilized
eggs from rhesus monkeys and cows the ubiquitination was evident at
first mitosis. The signal typically disappeared between the 4-cell and
the 8-cell stages of development. This ubiquitination also occurs in the
male reproductive tract, but the ubiquitinated sites are masked by
disulfide bonds during passage through the epididymis.
Conaway et al. (2002) reviewed the role of ubiquitin in transcription
regulation in both proteasome-dependent and proteasome-independent
mechanisms.
Cui et al. (2010) showed that Cif homolog from Burkholderia pseudomallei
(CHBP) was a potent inhibitor of the eukaryotic ubiquitination pathway
in human cells. CHBP acted as a deamidase that specifically and
efficiently deamidated gln40 in ubiquitin and ubiquitin-like protein
NEDD8 (603171) both in vitro and during Burkholderia infection.
Deamidated ubiquitin was impaired in supporting ubiquitin-chain
synthesis. Cif selectively deamidated NEDD8, which abolished the
activity of neddylated Cullin-RING ubiquitin ligases (CRLs).
Ubiquitination and ubiquitin-dependent degradation of multiple CRL
substrates were impaired by Cif in enteropathogenic E. coli
(EPEC)-infected cells. Mutations of substrate-contacting residues in Cif
abolished or attenuated EPEC-induced cytopathic phenotypes of cell cycle
arrest and actin stress fiber formation.
- Association of Ubiquitin With Disease
Lowe et al. (1988) discussed the role of ubiquitin in a variety of
neuropathologic conditions including Parkinson disease (see 168600),
Pick disease (see 172700), and Alzheimer disease (AD; 104300).
The protein deposits in neurofibrillary tangles, neuritic plaques, and
neuropil threads in the cerebral cortex of patients with Alzheimer
disease and Down syndrome (DS; 190685) contain forms of beta-amyloid
precursor protein (APP; 104760) and ubiquitin-B that are aberrant in the
C terminus. Based on studies of homozygous Brattleboro rats with
diabetes insipidus who show a GA deletion in a GAGAG motif in mRNA
transcripts of the vasopressin gene (192340), van Leeuwen et al. (1998)
postulated that a dinucleotide deletion (delta-GA, delta-GT, or
delta-CT) could occur in mRNA transcripts as a consequence of aging. The
authors found GAGAG motifs in UBB mRNA, and predicted that a +1
frameshift in APP (APP+1) or UBB (UBB+1) would result in a protein with
an aberrant C terminus, lacking the glycine residue essential for
multiubiquitylation. Immunoreactivity to UBB+1 and APP+1 was found in
brains from patients with early- and late-onset AD and Down syndrome.
The aberrant UBB+1 and APP+1 proteins were not found in young control
subjects but were present in elderly control patients. The aberrant
proteins were not found in patients with Parkinson disease. Van Leeuwen
et al. (1998) stated that the process is probably not limited to
postmitotic cells; however, postmitotic neurons are less capable of
compensating for transcript-modifying activity and are thus particularly
sensitive to the accumulation of frameshifted proteins. Thus, during
aging, single neurons may generate and accumulate abnormal proteins,
leading to cellular disturbances and causing degeneration.
Van Leeuwen et al. (2006) found that the aberrant APP+1 protein was
present in neurons with beaded fibers in young individuals with Down
syndrome in the absence of any pathologic hallmarks of AD. Both APP+1
and UBB+1 were present within brain neurofibrillary tangles and neuritic
plaques from older DS patients and patients with various forms of
autosomal dominant AD. Moreover, APP+1 and UBB+1 were detected in the
neuropathologic hallmarks of other tau (MAPT; 157140)-related dementias,
including Pick disease (172700), progressive supranuclear palsy (PSP;
601104), and less commonly frontotemporal dementia (FTD; 600274). Van
Leeuwen et al. (2006) postulated that accumulation of APP+1 and UBB+1
contributes to various forms of dementia.
Fratta et al. (2004) found that 70 to 80% of the vacuolated muscle
fibers in samples from 10 patients with sporadic inclusion body myositis
(147421) contained strong immunoreactivity to mutant ubiquitin (UBB+1)
in the form of numerous well-defined plaque-like, dotted, or elongated
aggregates. Similar aggregates were identified in 10 to 15% of the
nonvacuolated normal-appearing fibers. In the abnormal fibers, these
aggregates were concurrently immunoreactive for wildtype UBB and either
beta-amyloid or phosphorylated tau (MAPT; 157140). None of the control
biopsies were immunoreactive to UBB+1. Fratta et al. (2004) suggested
that the UBB+1-inhibited proteasome cannot properly degrade toxic
proteins, resulting in their accumulation and aggregation.
Tank and True (2009) expressed a protein analogous to UBB+1 in yeast
(Ubb(ext)) and demonstrated that it impaired the ubiquitin/proteasome
system. Ubb(ext) did not cause protein aggregation itself, but it
rendered yeast more susceptible to other toxic protein aggregates.
Ubb(ext) appeared to act as a modifier that altered substrate
ubiquitination and the function of the ubiquitin/proteasome system.
Smith-Magenis syndrome (SMS; 182290) is a syndrome exhibiting multiple
congenital anomalies and mental retardation, with distinctive behavioral
characteristics, sleep disturbance, and dysmorphic features, associated
with a heterozygous interstitial deletion of 17p11.2. Heterozygous
frameshift mutations of the RAI1 gene (607642) seem to be responsible
for most of the SMS features, but other deleted genes in the SMS region
may modify the overall phenotype. In a comparative genome hybridization
analysis of the short arm of chromosome 17 in 30 patients with SMS,
Andrieux et al. (2007) found that 3 had large deletions and that 2 of
these had cleft palate, which was not found in any of the other
patients. The smallest extra-deleted region associated with cleft palate
and SMS was 1.4 Mb, contained less than 16 genes, and was located at
17p12-p11.2. Gene expression array data showed that the UBB gene is
significantly expressed in the first branchial arch in the fourth and
fifth weeks of human development. Together, the data supported UBB as a
candidate gene for isolated cleft palate.
ANIMAL MODEL
Ryu et al. (2008) found that newborn Ubb-null mice were smaller than
wildtype or heterozygous littermates and exhibited subtle perinatal
linear growth retardation, but they were otherwise indistinguishable
from wildtype mice. However, Ubb deletion led to adult-onset obesity
that strongly correlated with selective degeneration of neurons that
control energy balance in the arcuate nucleus of the hypothalamus. Total
Ub levels were reduced in the hypothalamus of Ubb-null mice. Ryu et al.
(2008) concluded that adequate cellular UB is essential for neuronal
survival.
*FIELD* SA
Ecker et al. (1987)
*FIELD* RF
1. Andrieux, J.; Villenet, C.; Quief, S.; Lignon, S.; Geffroy, S.;
Roumier, C.; de Leersnyder, H.; de Blois, M.-C.; Manouvrier, S.; Delobel,
B.; Benzacken, B.; Bitoun, P.; Attie-Bitach, T.; Thomas, S.; Lyonnet,
S.; Vekemans, M.; Kerckaert, J.-P.: Genotype-phenotype correlation
of 30 patients with Smith-Magenis syndrome (SMS) using comparative
genome hybridisation array: cleft palate in SMS is associated with
larger deletions. (Letter) J. Med. Genet. 44: 537-540, 2007.
2. Baker, R. T.; Board, P. G.: The human ubiquitin gene family: structure
of a gene and pseudogenes from the Ub B subfamily. Nucleic Acids
Res. 15: 443-463, 1987.
3. Conaway, R. C.; Brower, C. S.; Conaway, J. W.: Emerging roles
of ubiquitin in transcription regulation. Science 296: 1254-1258,
2002.
4. Cui, J.; Yao, Q.; Li, S.; Ding, X.; Lu, Q.; Mao, H.; Liu, L.; Zheng,
N.; Chen, S.; Shao, F.: Glutamine deamidation and dysfunction of
ubiquitin/NEDD8 induced by a bacterial effector family. Science 329:
1215-1218, 2010.
5. Ecker, D. J.; Butt, T. R.; Marsh, J.; Sternberg, E. J.; Margolis,
N.; Monia, B. P.; Jonnalagadda, S.; Khan, M. I.; Weber, P. L.; Mueller,
L.; Crooke, S. T.: Gene synthesis, expression, structures, and functional
activities of site-specific mutants of ubiquitin. J. Biol. Chem. 262:
14213-14221, 1987.
6. Finley, D.; Bartel, B.; Varshavsky, A.: The tails of ubiquitin
precursors are ribosomal proteins whose fusion to ubiquitin facilitates
ribosome biogenesis. Nature 338: 394-401, 1989.
7. Fratta, P.; Engel, W. K.; Van Leeuwen, F. W.; Hol, E. M.; Vattemi,
G.; Askanas, V.: Mutant ubiquitin UBB+1 is accumulated in sporadic
inclusion-body myositis muscle fibers. Neurology 63: 1114-1117,
2004.
8. Lowe, J.; Blanchard, A.; Morrell, K.; Lennox, G.; Reynolds, L.;
Billett, M.; Landon, M.; Mayer, R. J.: Ubiquitin is a common factor
in intermediate filament inclusion bodies of diverse type in man,
including those of Parkinson's disease, Pick's disease, and Alzheimer's
disease, as well as Rosenthal fibres in cerebellar astrocytomas, cytoplasmic
bodies in muscle, and Mallory bodies in alcoholic liver disease. J.
Path. 155: 9-15, 1988.
9. Redman, K. L.; Rechsteiner, M.: Identification of the long ubiquitin
extension as ribosomal protein S27a. Nature 338: 438-440, 1989.
10. Ryu, K.-Y.; Garza, J. C.; Lu, X.-Y.; Barsh, G. S.; Kopito, R.
R.: Hypothalamic neurodegeneration and adult-onset obesity in mice
lacking the Ubb polyubiquitin gene. Proc. Nat. Acad. Sci. 105: 4016-4021,
2008.
11. Sutovsky, P.; Moreno, R. D.; Ramalho-Santos, J.; Dominko, T.;
Simerly, C.; Schatten, G.: Ubiquitin tag for sperm mitochondria. Nature 402:
371-372, 1999.
12. Tank, E. M. H.; True, H. L.: Disease-associated mutant ubiquitin
causes proteasomal impairment and enhances the toxicity of protein
aggregates. PLoS Genet. 5: e1000382 only, 2009. Note: Electronic
Article.
13. van Leeuwen, F. W.; de Kleijn, D. P. V.; van den Hurk, H. H.;
Neubauer, A.; Sonnemans, M. A. F.; Sluijs, J. A.; Koycu, S.; Ramdjielal,
R. D. J.; Salehi, A.; Martens, G. J. M.; Grosveld, F. G.; Burbach,
J. P. H.; Hol, E. M.: Frameshift mutants of beta-amyloid precursor
protein and ubiquitin-B in Alzheimer's and Down patients. Science 279:
242-247, 1998.
14. van Leeuwen, F. W.; van Tijn, P.; Sonnemans, M. A. F.; Hobo, B.;
Mann, D. M. A.; Van Broeckhoven, C.; Kumar-Singh, S.; Cras, P.; Leuba,
G.; Savioz, A.; Maat-Schieman, M. L. C.; Yamaguchi, H.; Kros, J. M.;
Kamphorst, W.; Hol, E. M.; de Vos, R. A. I.; Fischer, D. F.: Frameshift
proteins in autosomal dominant forms of Alzheimer disease and other
tauopathies. Neurology 66 (suppl. 1): S86-S92, 2006.
15. Webb, G. C.; Baker, R. T.; Fagan, K.; Board, P. G.: Localization
of the human UbB polyubiquitin gene to chromosome band 17p11.1-17p12. Am.
J. Hum. Genet. 46: 308-315, 1990.
16. Wiborg, O.; Pedersen, M. S.; Wind, A.; Berglund, L. E.; Marcker,
K. A.; Vuust, J.: The human ubiquitin multigene family: some genes
contain multiple directly repeated ubiquitin coding sequences. EMBO
J. 4: 755-759, 1985.
*FIELD* CN
Ada Hamosh - updated: 10/28/2010
Patricia A. Hartz - updated: 2/19/2010
Patricia A. Hartz - updated: 5/29/2008
Victor A. McKusick - updated: 12/28/2007
Cassandra L. Kniffin - updated: 4/18/2006
Cassandra L. Kniffin - updated: 4/12/2005
Victor A. McKusick - updated: 1/21/1998
*FIELD* CD
Victor A. McKusick: 2/27/1990
*FIELD* ED
carol: 12/09/2010
terry: 11/30/2010
alopez: 10/28/2010
mgross: 2/24/2010
terry: 2/19/2010
mgross: 6/10/2008
terry: 5/29/2008
alopez: 1/25/2008
terry: 12/28/2007
carol: 12/26/2007
carol: 5/14/2007
wwang: 4/24/2006
ckniffin: 4/18/2006
wwang: 4/19/2005
wwang: 4/14/2005
ckniffin: 4/12/2005
carol: 9/9/2003
mark: 1/25/1998
terry: 1/21/1998
mark: 2/20/1997
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 2/27/1990
*RECORD*
*FIELD* NO
191339
*FIELD* TI
*191339 UBIQUITIN B; UBB
;;POLYUBIQUITIN B
*FIELD* TX
DESCRIPTION
Ubiquitin, a small protein consisting of 76 amino acids, has been found
read morein all eukaryotic cells studied. It is one of the most conserved
proteins known; the amino acid sequence is identical from insects to
humans, and there are only 3 substitutions within the plant and yeast
sequences. Two classes of ubiquitin genes are recognized. Class I is a
polyubiquitin gene, such as UBB or UBC (191340), encoding a polyprotein
of tandemly repeated ubiquitins. The class II genes are fusion products
between a single ubiquitin gene and 1 of 2 other possible sequences,
either 52 or 76 to 80 predominantly basic amino acids (see UBA52,
191321, and UBA80, 191343, respectively). Ubiquitin is required for
ATP-dependent, nonlysosomal intracellular protein degradation, which
eliminates most intracellular defective problems as well as normal
proteins with a rapid turnover. Degradation involves covalent binding of
ubiquitin to the protein to be degraded, through isopeptide bonds from
the C-terminal glycine residue to the epsilon-amino groups of lysyl side
chains. Presumably, the function of ubiquitin is to label the protein
for disposal by intracellular proteases. The most abundant
ubiquitin-protein conjugate, however, is ubiquitin-H2A, in which
ubiquitin is bound to lys119 in histone H2A; this conjugate is not
degraded. Since such ubiquitinated histones are present primarily in
actively transcribed chromosomal regions, ubiquitin may play a role in
regulation of gene expression (summary by Wiborg et al. (1985) and Baker
and Board (1987)).
CLONING
Wiborg et al. (1985) determined that ubiquitin is encoded as a multigene
family.
Baker and Board (1987) studied cDNA and genomic clones of ubiquitin.
MAPPING
By in situ hybridization, Webb et al. (1990) assigned the 3-coding unit
polyubiquitin gene UBB and its nonprocessed pseudogene to chromosome
17p12-p11.1.
GENE FUNCTION
Finley et al. (1989) demonstrated that the basic amino acids fused to
ubiquitin in the class II gene products represent ribosomal proteins,
and that their fusion to ubiquitin performs a crucial role in ribosome
biogenesis in the Saccharomyces cerevisiae. Redman and Rechsteiner
(1989) studied these 3-prime in-frame extensions of the ubiquitin genes
in mammalian systems and concluded, as did Finley et al. (1989), that
the C-terminal extension proteins are ribosomal components.
Sutovsky et al. (1999) demonstrated that sperm mitochondria are
selectively marked for destruction by a ubiquitin tag. In fertilized
eggs from rhesus monkeys and cows the ubiquitination was evident at
first mitosis. The signal typically disappeared between the 4-cell and
the 8-cell stages of development. This ubiquitination also occurs in the
male reproductive tract, but the ubiquitinated sites are masked by
disulfide bonds during passage through the epididymis.
Conaway et al. (2002) reviewed the role of ubiquitin in transcription
regulation in both proteasome-dependent and proteasome-independent
mechanisms.
Cui et al. (2010) showed that Cif homolog from Burkholderia pseudomallei
(CHBP) was a potent inhibitor of the eukaryotic ubiquitination pathway
in human cells. CHBP acted as a deamidase that specifically and
efficiently deamidated gln40 in ubiquitin and ubiquitin-like protein
NEDD8 (603171) both in vitro and during Burkholderia infection.
Deamidated ubiquitin was impaired in supporting ubiquitin-chain
synthesis. Cif selectively deamidated NEDD8, which abolished the
activity of neddylated Cullin-RING ubiquitin ligases (CRLs).
Ubiquitination and ubiquitin-dependent degradation of multiple CRL
substrates were impaired by Cif in enteropathogenic E. coli
(EPEC)-infected cells. Mutations of substrate-contacting residues in Cif
abolished or attenuated EPEC-induced cytopathic phenotypes of cell cycle
arrest and actin stress fiber formation.
- Association of Ubiquitin With Disease
Lowe et al. (1988) discussed the role of ubiquitin in a variety of
neuropathologic conditions including Parkinson disease (see 168600),
Pick disease (see 172700), and Alzheimer disease (AD; 104300).
The protein deposits in neurofibrillary tangles, neuritic plaques, and
neuropil threads in the cerebral cortex of patients with Alzheimer
disease and Down syndrome (DS; 190685) contain forms of beta-amyloid
precursor protein (APP; 104760) and ubiquitin-B that are aberrant in the
C terminus. Based on studies of homozygous Brattleboro rats with
diabetes insipidus who show a GA deletion in a GAGAG motif in mRNA
transcripts of the vasopressin gene (192340), van Leeuwen et al. (1998)
postulated that a dinucleotide deletion (delta-GA, delta-GT, or
delta-CT) could occur in mRNA transcripts as a consequence of aging. The
authors found GAGAG motifs in UBB mRNA, and predicted that a +1
frameshift in APP (APP+1) or UBB (UBB+1) would result in a protein with
an aberrant C terminus, lacking the glycine residue essential for
multiubiquitylation. Immunoreactivity to UBB+1 and APP+1 was found in
brains from patients with early- and late-onset AD and Down syndrome.
The aberrant UBB+1 and APP+1 proteins were not found in young control
subjects but were present in elderly control patients. The aberrant
proteins were not found in patients with Parkinson disease. Van Leeuwen
et al. (1998) stated that the process is probably not limited to
postmitotic cells; however, postmitotic neurons are less capable of
compensating for transcript-modifying activity and are thus particularly
sensitive to the accumulation of frameshifted proteins. Thus, during
aging, single neurons may generate and accumulate abnormal proteins,
leading to cellular disturbances and causing degeneration.
Van Leeuwen et al. (2006) found that the aberrant APP+1 protein was
present in neurons with beaded fibers in young individuals with Down
syndrome in the absence of any pathologic hallmarks of AD. Both APP+1
and UBB+1 were present within brain neurofibrillary tangles and neuritic
plaques from older DS patients and patients with various forms of
autosomal dominant AD. Moreover, APP+1 and UBB+1 were detected in the
neuropathologic hallmarks of other tau (MAPT; 157140)-related dementias,
including Pick disease (172700), progressive supranuclear palsy (PSP;
601104), and less commonly frontotemporal dementia (FTD; 600274). Van
Leeuwen et al. (2006) postulated that accumulation of APP+1 and UBB+1
contributes to various forms of dementia.
Fratta et al. (2004) found that 70 to 80% of the vacuolated muscle
fibers in samples from 10 patients with sporadic inclusion body myositis
(147421) contained strong immunoreactivity to mutant ubiquitin (UBB+1)
in the form of numerous well-defined plaque-like, dotted, or elongated
aggregates. Similar aggregates were identified in 10 to 15% of the
nonvacuolated normal-appearing fibers. In the abnormal fibers, these
aggregates were concurrently immunoreactive for wildtype UBB and either
beta-amyloid or phosphorylated tau (MAPT; 157140). None of the control
biopsies were immunoreactive to UBB+1. Fratta et al. (2004) suggested
that the UBB+1-inhibited proteasome cannot properly degrade toxic
proteins, resulting in their accumulation and aggregation.
Tank and True (2009) expressed a protein analogous to UBB+1 in yeast
(Ubb(ext)) and demonstrated that it impaired the ubiquitin/proteasome
system. Ubb(ext) did not cause protein aggregation itself, but it
rendered yeast more susceptible to other toxic protein aggregates.
Ubb(ext) appeared to act as a modifier that altered substrate
ubiquitination and the function of the ubiquitin/proteasome system.
Smith-Magenis syndrome (SMS; 182290) is a syndrome exhibiting multiple
congenital anomalies and mental retardation, with distinctive behavioral
characteristics, sleep disturbance, and dysmorphic features, associated
with a heterozygous interstitial deletion of 17p11.2. Heterozygous
frameshift mutations of the RAI1 gene (607642) seem to be responsible
for most of the SMS features, but other deleted genes in the SMS region
may modify the overall phenotype. In a comparative genome hybridization
analysis of the short arm of chromosome 17 in 30 patients with SMS,
Andrieux et al. (2007) found that 3 had large deletions and that 2 of
these had cleft palate, which was not found in any of the other
patients. The smallest extra-deleted region associated with cleft palate
and SMS was 1.4 Mb, contained less than 16 genes, and was located at
17p12-p11.2. Gene expression array data showed that the UBB gene is
significantly expressed in the first branchial arch in the fourth and
fifth weeks of human development. Together, the data supported UBB as a
candidate gene for isolated cleft palate.
ANIMAL MODEL
Ryu et al. (2008) found that newborn Ubb-null mice were smaller than
wildtype or heterozygous littermates and exhibited subtle perinatal
linear growth retardation, but they were otherwise indistinguishable
from wildtype mice. However, Ubb deletion led to adult-onset obesity
that strongly correlated with selective degeneration of neurons that
control energy balance in the arcuate nucleus of the hypothalamus. Total
Ub levels were reduced in the hypothalamus of Ubb-null mice. Ryu et al.
(2008) concluded that adequate cellular UB is essential for neuronal
survival.
*FIELD* SA
Ecker et al. (1987)
*FIELD* RF
1. Andrieux, J.; Villenet, C.; Quief, S.; Lignon, S.; Geffroy, S.;
Roumier, C.; de Leersnyder, H.; de Blois, M.-C.; Manouvrier, S.; Delobel,
B.; Benzacken, B.; Bitoun, P.; Attie-Bitach, T.; Thomas, S.; Lyonnet,
S.; Vekemans, M.; Kerckaert, J.-P.: Genotype-phenotype correlation
of 30 patients with Smith-Magenis syndrome (SMS) using comparative
genome hybridisation array: cleft palate in SMS is associated with
larger deletions. (Letter) J. Med. Genet. 44: 537-540, 2007.
2. Baker, R. T.; Board, P. G.: The human ubiquitin gene family: structure
of a gene and pseudogenes from the Ub B subfamily. Nucleic Acids
Res. 15: 443-463, 1987.
3. Conaway, R. C.; Brower, C. S.; Conaway, J. W.: Emerging roles
of ubiquitin in transcription regulation. Science 296: 1254-1258,
2002.
4. Cui, J.; Yao, Q.; Li, S.; Ding, X.; Lu, Q.; Mao, H.; Liu, L.; Zheng,
N.; Chen, S.; Shao, F.: Glutamine deamidation and dysfunction of
ubiquitin/NEDD8 induced by a bacterial effector family. Science 329:
1215-1218, 2010.
5. Ecker, D. J.; Butt, T. R.; Marsh, J.; Sternberg, E. J.; Margolis,
N.; Monia, B. P.; Jonnalagadda, S.; Khan, M. I.; Weber, P. L.; Mueller,
L.; Crooke, S. T.: Gene synthesis, expression, structures, and functional
activities of site-specific mutants of ubiquitin. J. Biol. Chem. 262:
14213-14221, 1987.
6. Finley, D.; Bartel, B.; Varshavsky, A.: The tails of ubiquitin
precursors are ribosomal proteins whose fusion to ubiquitin facilitates
ribosome biogenesis. Nature 338: 394-401, 1989.
7. Fratta, P.; Engel, W. K.; Van Leeuwen, F. W.; Hol, E. M.; Vattemi,
G.; Askanas, V.: Mutant ubiquitin UBB+1 is accumulated in sporadic
inclusion-body myositis muscle fibers. Neurology 63: 1114-1117,
2004.
8. Lowe, J.; Blanchard, A.; Morrell, K.; Lennox, G.; Reynolds, L.;
Billett, M.; Landon, M.; Mayer, R. J.: Ubiquitin is a common factor
in intermediate filament inclusion bodies of diverse type in man,
including those of Parkinson's disease, Pick's disease, and Alzheimer's
disease, as well as Rosenthal fibres in cerebellar astrocytomas, cytoplasmic
bodies in muscle, and Mallory bodies in alcoholic liver disease. J.
Path. 155: 9-15, 1988.
9. Redman, K. L.; Rechsteiner, M.: Identification of the long ubiquitin
extension as ribosomal protein S27a. Nature 338: 438-440, 1989.
10. Ryu, K.-Y.; Garza, J. C.; Lu, X.-Y.; Barsh, G. S.; Kopito, R.
R.: Hypothalamic neurodegeneration and adult-onset obesity in mice
lacking the Ubb polyubiquitin gene. Proc. Nat. Acad. Sci. 105: 4016-4021,
2008.
11. Sutovsky, P.; Moreno, R. D.; Ramalho-Santos, J.; Dominko, T.;
Simerly, C.; Schatten, G.: Ubiquitin tag for sperm mitochondria. Nature 402:
371-372, 1999.
12. Tank, E. M. H.; True, H. L.: Disease-associated mutant ubiquitin
causes proteasomal impairment and enhances the toxicity of protein
aggregates. PLoS Genet. 5: e1000382 only, 2009. Note: Electronic
Article.
13. van Leeuwen, F. W.; de Kleijn, D. P. V.; van den Hurk, H. H.;
Neubauer, A.; Sonnemans, M. A. F.; Sluijs, J. A.; Koycu, S.; Ramdjielal,
R. D. J.; Salehi, A.; Martens, G. J. M.; Grosveld, F. G.; Burbach,
J. P. H.; Hol, E. M.: Frameshift mutants of beta-amyloid precursor
protein and ubiquitin-B in Alzheimer's and Down patients. Science 279:
242-247, 1998.
14. van Leeuwen, F. W.; van Tijn, P.; Sonnemans, M. A. F.; Hobo, B.;
Mann, D. M. A.; Van Broeckhoven, C.; Kumar-Singh, S.; Cras, P.; Leuba,
G.; Savioz, A.; Maat-Schieman, M. L. C.; Yamaguchi, H.; Kros, J. M.;
Kamphorst, W.; Hol, E. M.; de Vos, R. A. I.; Fischer, D. F.: Frameshift
proteins in autosomal dominant forms of Alzheimer disease and other
tauopathies. Neurology 66 (suppl. 1): S86-S92, 2006.
15. Webb, G. C.; Baker, R. T.; Fagan, K.; Board, P. G.: Localization
of the human UbB polyubiquitin gene to chromosome band 17p11.1-17p12. Am.
J. Hum. Genet. 46: 308-315, 1990.
16. Wiborg, O.; Pedersen, M. S.; Wind, A.; Berglund, L. E.; Marcker,
K. A.; Vuust, J.: The human ubiquitin multigene family: some genes
contain multiple directly repeated ubiquitin coding sequences. EMBO
J. 4: 755-759, 1985.
*FIELD* CN
Ada Hamosh - updated: 10/28/2010
Patricia A. Hartz - updated: 2/19/2010
Patricia A. Hartz - updated: 5/29/2008
Victor A. McKusick - updated: 12/28/2007
Cassandra L. Kniffin - updated: 4/18/2006
Cassandra L. Kniffin - updated: 4/12/2005
Victor A. McKusick - updated: 1/21/1998
*FIELD* CD
Victor A. McKusick: 2/27/1990
*FIELD* ED
carol: 12/09/2010
terry: 11/30/2010
alopez: 10/28/2010
mgross: 2/24/2010
terry: 2/19/2010
mgross: 6/10/2008
terry: 5/29/2008
alopez: 1/25/2008
terry: 12/28/2007
carol: 12/26/2007
carol: 5/14/2007
wwang: 4/24/2006
ckniffin: 4/18/2006
wwang: 4/19/2005
wwang: 4/14/2005
ckniffin: 4/12/2005
carol: 9/9/2003
mark: 1/25/1998
terry: 1/21/1998
mark: 2/20/1997
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 2/27/1990