BAG6_ORNAN
ID BAG6_ORNAN Reviewed; 1088 AA.
AC A7X5R6;
DT 11-JAN-2011, integrated into UniProtKB/Swiss-Prot.
DT 23-OCT-2007, sequence version 1.
DT 25-MAY-2022, entry version 72.
DE RecName: Full=Large proline-rich protein BAG6 {ECO:0000305};
DE AltName: Full=BCL2-associated athanogene 6 {ECO:0000250|UniProtKB:P46379};
DE AltName: Full=HLA-B-associated transcript 3 {ECO:0000250|UniProtKB:P46379};
GN Name=BAG6 {ECO:0000250|UniProtKB:P46379};
GN Synonyms=BAT3 {ECO:0000250|UniProtKB:P46379};
OS Ornithorhynchus anatinus (Duckbill platypus).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Monotremata; Ornithorhynchidae; Ornithorhynchus.
OX NCBI_TaxID=9258;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=17727704; DOI=10.1186/gb-2007-8-8-r175;
RA Dohm J.C., Tsend-Ayush E., Reinhardt R., Grutzner F., Himmelbauer H.;
RT "Disruption and pseudoautosomal localization of the major
RT histocompatibility complex in monotremes.";
RL Genome Biol. 8:R175.1-R175.16(2007).
CC -!- FUNCTION: ATP-independent molecular chaperone preventing the
CC aggregation of misfolded and hydrophobic patches-containing proteins.
CC Functions as part of a cytosolic protein quality control complex, the
CC BAG6/BAT3 complex, which maintains these client proteins in a soluble
CC state and participates in their proper delivery to the endoplasmic
CC reticulum or alternatively can promote their sorting to the proteasome
CC where they undergo degradation. The BAG6/BAT3 complex is involved in
CC the post-translational delivery of tail-anchored/type II transmembrane
CC proteins to the endoplasmic reticulum membrane. Recruited to ribosomes,
CC it interacts with the transmembrane region of newly synthesized tail-
CC anchored proteins and together with SGTA and ASNA1 mediates their
CC delivery to the endoplasmic reticulum. Client proteins that cannot be
CC properly delivered to the endoplasmic reticulum are ubiquitinated by
CC RNF126, an E3 ubiquitin-protein ligase associated with BAG6 and are
CC sorted to the proteasome. SGTA which prevents the recruitment of RNF126
CC to BAG6 may negatively regulate the ubiquitination and the proteasomal
CC degradation of client proteins. Similarly, the BAG6/BAT3 complex also
CC functions as a sorting platform for proteins of the secretory pathway
CC that are mislocalized to the cytosol either delivering them to the
CC proteasome for degradation or to the endoplasmic reticulum. The
CC BAG6/BAT3 complex also plays a role in the endoplasmic reticulum-
CC associated degradation (ERAD), a quality control mechanism that
CC eliminates unwanted proteins of the endoplasmic reticulum through their
CC retrotranslocation to the cytosol and their targeting to the
CC proteasome. It maintains these retrotranslocated proteins in an
CC unfolded yet soluble state condition in the cytosol to ensure their
CC proper delivery to the proteasome. BAG6 is also required for selective
CC ubiquitin-mediated degradation of defective nascent chain polypeptides
CC by the proteasome. In this context, it may participate in the
CC production of antigenic peptides and play a role in antigen
CC presentation in immune response. BAG6 is also involved in endoplasmic
CC reticulum stress-induced pre-emptive quality control, a mechanism that
CC selectively attenuates the translocation of newly synthesized proteins
CC into the endoplasmic reticulum and reroutes them to the cytosol for
CC proteasomal degradation. BAG6 may ensure the proper degradation of
CC these proteins and thereby protects the endoplasmic reticulum from
CC protein overload upon stress. By inhibiting the polyubiquitination and
CC subsequent proteasomal degradation of HSPA2 it may also play a role in
CC the assembly of the synaptonemal complex during spermatogenesis. Also
CC positively regulates apoptosis by interacting with and stabilizing the
CC proapoptotic factor AIFM1. By controlling the steady-state expression
CC of the IGF1R receptor, indirectly regulates the insulin-like growth
CC factor receptor signaling pathway. {ECO:0000250|UniProtKB:P46379}.
CC -!- FUNCTION: Involved in DNA damage-induced apoptosis: following DNA
CC damage, accumulates in the nucleus and forms a complex with p300/EP300,
CC enhancing p300/EP300-mediated p53/TP53 acetylation leading to increase
CC p53/TP53 transcriptional activity. When nuclear, may also act as a
CC component of some chromatin regulator complex that regulates histone 3
CC 'Lys-4' dimethylation (H3K4me2). {ECO:0000250|UniProtKB:P46379}.
CC -!- FUNCTION: Released extracellularly via exosomes, it is a ligand of the
CC natural killer/NK cells receptor NCR3 and stimulates NK cells
CC cytotoxicity. It may thereby trigger NK cells cytotoxicity against
CC neighboring tumor cells and immature myeloid dendritic cells (DC).
CC {ECO:0000250|UniProtKB:P46379}.
CC -!- FUNCTION: May mediate ricin-induced apoptosis.
CC {ECO:0000250|UniProtKB:P46379}.
CC -!- SUBUNIT: Component of the BAG6/BAT3 complex, also named BAT3 complex,
CC at least composed of BAG6, UBL4A and GET4/TRC35. Interacts with GET4;
CC the interaction is direct and localizes BAG6 in the cytosol. Interacts
CC with UBL4A; the interaction is direct and required for UBL4A protein
CC stability. Interacts with AIFM1. Interacts with HSPA2. Interacts with
CC CTCFL. Interacts with p300/EP300. Interacts (via ubiquitin-like domain)
CC with RNF126; required for BAG6-dependent ubiquitination of proteins
CC mislocalized to the cytosol. Interacts (via ubiquitin-like domain) with
CC SGTA; SGTA competes with RNF126 by binding the same region of BAG6,
CC thereby promoting deubiquitination of BAG6-target proteins and rescuing
CC them from degradation. Interacts with ricin A chain. Interacts with VCP
CC and AMFR; both form the VCP/p97-AMFR/gp78 complex. Interacts with
CC SYVN1. Interacts with USP13; the interaction is direct and may mediate
CC UBL4A deubiquitination. Interacts with ZFAND2B. Interacts with KPNA2.
CC Interacts with UBQLN4 (By similarity). {ECO:0000250|UniProtKB:P46379,
CC ECO:0000250|UniProtKB:Q9Z1R2}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:P46379}. Nucleus {ECO:0000250|UniProtKB:P46379}.
CC Secreted, extracellular exosome {ECO:0000250|UniProtKB:P46379}.
CC Note=Normally localized in cytosol and nucleus, it can also be released
CC extracellularly, in exosomes, by tumor and myeloid dendritic cells.
CC {ECO:0000250|UniProtKB:P46379}.
CC -!- DOMAIN: The ubiquitin-like domain mediates interaction with the E3
CC ubiquitin-protein ligase RNF126 which is responsible for the BAG6-
CC dependent ubiquitination of client proteins. SGTA also binds this
CC domain and competes with RNF126 to antagonize client protein
CC ubiquitination and degradation. The ubiquitin-like domain also mediates
CC the interaction with USP13. {ECO:0000250|UniProtKB:P46379}.
CC -!- PTM: Ricin can induce the cleavage by the caspase CASP3.
CC {ECO:0000250|UniProtKB:P46379}.
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DR EMBL; EU030444; ABU86908.1; -; Genomic_DNA.
DR RefSeq; NP_001229675.1; NM_001242746.1.
DR AlphaFoldDB; A7X5R6; -.
DR SMR; A7X5R6; -.
DR STRING; 9258.ENSOANP00000032214; -.
DR GeneID; 100529065; -.
DR KEGG; oaa:100529065; -.
DR CTD; 7917; -.
DR eggNOG; KOG4248; Eukaryota.
DR InParanoid; A7X5R6; -.
DR OrthoDB; 1233552at2759; -.
DR Proteomes; UP000002279; Unplaced.
DR GO; GO:0071818; C:BAT3 complex; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0051787; F:misfolded protein binding; IBA:GO_Central.
DR GO; GO:0031593; F:polyubiquitin modification-dependent protein binding; ISS:UniProtKB.
DR GO; GO:0070628; F:proteasome binding; ISS:UniProtKB.
DR GO; GO:0043022; F:ribosome binding; ISS:UniProtKB.
DR GO; GO:0007420; P:brain development; ISS:UniProtKB.
DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR GO; GO:0006325; P:chromatin organization; IEA:UniProtKB-KW.
DR GO; GO:0061857; P:endoplasmic reticulum stress-induced pre-emptive quality control; ISS:UniProtKB.
DR GO; GO:0071712; P:ER-associated misfolded protein catabolic process; ISS:UniProtKB.
DR GO; GO:0002376; P:immune system process; IEA:UniProtKB-KW.
DR GO; GO:0018393; P:internal peptidyl-lysine acetylation; ISS:UniProtKB.
DR GO; GO:0042771; P:intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator; ISS:UniProtKB.
DR GO; GO:0070059; P:intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; ISS:UniProtKB.
DR GO; GO:0001822; P:kidney development; ISS:UniProtKB.
DR GO; GO:0030324; P:lung development; ISS:UniProtKB.
DR GO; GO:0032435; P:negative regulation of proteasomal ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR GO; GO:0045861; P:negative regulation of proteolysis; ISS:UniProtKB.
DR GO; GO:0010498; P:proteasomal protein catabolic process; ISS:UniProtKB.
DR GO; GO:0050821; P:protein stabilization; ISS:UniProtKB.
DR GO; GO:0042981; P:regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0045995; P:regulation of embryonic development; ISS:UniProtKB.
DR GO; GO:0007283; P:spermatogenesis; ISS:UniProtKB.
DR GO; GO:0007130; P:synaptonemal complex assembly; ISS:UniProtKB.
DR GO; GO:0071816; P:tail-anchored membrane protein insertion into ER membrane; ISS:UniProtKB.
DR GO; GO:0030433; P:ubiquitin-dependent ERAD pathway; ISS:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR InterPro; IPR021925; BAG6.
DR InterPro; IPR000626; Ubiquitin-like_dom.
DR InterPro; IPR029071; Ubiquitin-like_domsf.
DR InterPro; IPR019954; Ubiquitin_CS.
DR Pfam; PF12057; BAG6; 1.
DR Pfam; PF00240; ubiquitin; 1.
DR SMART; SM00213; UBQ; 1.
DR SUPFAM; SSF54236; SSF54236; 1.
DR PROSITE; PS00299; UBIQUITIN_1; 1.
DR PROSITE; PS50053; UBIQUITIN_2; 1.
PE 3: Inferred from homology;
KW Acetylation; Apoptosis; Chaperone; Chromatin regulator; Cytoplasm;
KW Differentiation; Immunity; Nucleus; Phosphoprotein; Reference proteome;
KW Repeat; Secreted; Spermatogenesis; Transport.
FT CHAIN 1..1088
FT /note="Large proline-rich protein BAG6"
FT /id="PRO_0000403750"
FT DOMAIN 24..99
FT /note="Ubiquitin-like"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00214"
FT REPEAT 243..274
FT /note="1"
FT /evidence="ECO:0000250|UniProtKB:P46379"
FT REPEAT 415..442
FT /note="2"
FT /evidence="ECO:0000250|UniProtKB:P46379"
FT REPEAT 571..599
FT /note="3"
FT /evidence="ECO:0000250|UniProtKB:P46379"
FT REPEAT 607..640
FT /note="4"
FT /evidence="ECO:0000250|UniProtKB:P46379"
FT REGION 1..23
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 94..136
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 193..276
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 243..640
FT /note="4 X 29 AA approximate repeats"
FT /evidence="ECO:0000250|UniProtKB:P46379"
FT REGION 390..440
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 459..491
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 503..528
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 557..603
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 655..700
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 945..1088
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1015..1045
FT /note="Required for interaction with GET4"
FT /evidence="ECO:0000250|UniProtKB:P46379"
FT REGION 1027..1088
FT /note="Sufficient for the delivery of client proteins to
FT the endoplasmic reticulum"
FT /evidence="ECO:0000250|UniProtKB:P46379"
FT COMPBIAS 194..210
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 230..248
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 257..271
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 390..416
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 417..438
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 460..485
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 505..525
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 567..583
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 585..602
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 658..689
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 1005..1006
FT /note="Cleavage; by CASP3"
FT /evidence="ECO:0000250|UniProtKB:P46379"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0000250|UniProtKB:P46379"
FT MOD_RES 103
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P46379"
FT MOD_RES 354
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P46379"
FT MOD_RES 976
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P46379"
FT MOD_RES 1073
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P46379"
SQ SEQUENCE 1088 AA; 112586 MW; 59144DCD0731671B CRC64;
MDPGGGGGGG GPGPGPDMEE PADLEVSVKT LDSQTRTFTV GAEMTVKEFK EHIAAAVSIP
PDKQRLIYQG RVLQDDKKLQ EYNVGGKVIH LVERAPPQTQ GPSSGGASRA GSPSAPHAGA
PPAGPRGPGA PVHDRNANSY VMVGTFNLPS DGSAVDVHIN MEQAPIQSEP RVRLVMAQHM
LRDIQALLAR LEPQPGQQGQ QGQQQGQALL AESGPPRPGP PGQTDGETSP REPTETREPT
ETREPEDGVA ARGTGPAPGP APAPAPEGNA APNHPSPAEY AEVLQELQRV ESRLQPFLQR
YRAILGAAAT TDYNNNTEGR EEDQRVINLV GESLRLLGNT FVALSDLRCN LSATAPRHLH
VVRPMSHYTA PMVLQQAAIP IQINVGTTVT MTGSGARPGP TDTTPTSGQT SSPTPSPTSG
EPGPDGAPSG PAPPQAAGPP RLIRISHQSV EPVVMMHMNI PDSGSQTGGT SSASTASTGL
PGQGLGQQVS GFPAAPTRVV IARPTPPQAR PPHPGGPPPA PGATIPVPGS NASLAQMVSG
LVGQLLMQPV LVAQGASGLG APQAPATASA SAGTTNTATT AGPAPGGPAQ PPPPPPPGPP
QAEVQFSQLL GSLLGPGVPG GPGTAGGATS VGSPTITVAM PGVPAFLQGM TDFLQATQTA
PPPPPPPPPP PAPEQAPAAA PPGSPPAGPG GAGGGPEALP PEFFTSVVQG VLSSLLGSLG
ARAGSGESIA GFIQRLSGSS NIFEPGADGA LGFFGALLSV ICQNLSMVDV VMLLHGHSQP
LQRLQPQLRG FFHQHYLGGR EPTGPAIRRA THTLITGLEE YVRDSFASVQ VQPGVDITRT
NLDFLQEQFN GIAAHVLHCT DSSFGVRLLE LCNQGLFECL ALNLHCLGGQ QSALTNVING
RIRRLSGGVN PSLVSWLTTM MGLRLQVVLE HMPVGPDQVL RYVRRLGEPP QPPPEEPMDV
QGAERAPPEP ERENASPAPG TTAEEAMSRG PPPAPEGPPP LEEQDGAAAA ESEPWAAAVP
PEWVPIIRQD LQTQRKVKPQ PPLSDAYLSG MPAKRRKLRS DLQQRLRADP NYSPQHFPNA
QRAFMDEP
