ID BAG5_HUMAN Reviewed; 447 AA. AC Q9UL15; O94950; Q86W59; DT 11-JAN-2001, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-2000, sequence version 1. DT 27-MAR-2024, entry version 187. DE RecName: Full=BAG family molecular chaperone regulator 5; DE Short=BAG-5; DE AltName: Full=Bcl-2-associated athanogene 5; GN Name=BAG5; Synonyms=KIAA0873; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=9873016; DOI=10.1074/jbc.274.2.781; RA Takayama S., Xie Z., Reed J.C.; RT "An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone RT regulators."; RL J. Biol. Chem. 274:781-786(1999). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RX PubMed=10048485; DOI=10.1093/dnares/5.6.355; RA Nagase T., Ishikawa K., Suyama M., Kikuno R., Hirosawa M., Miyajima N., RA Tanaka A., Kotani H., Nomura N., Ohara O.; RT "Prediction of the coding sequences of unidentified human genes. XII. The RT complete sequences of 100 new cDNA clones from brain which code for large RT proteins in vitro."; RL DNA Res. 5:355-364(1998). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12508121; DOI=10.1038/nature01348; RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C., RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A., RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H., RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T., RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B., RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D., RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R., RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S., RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C., RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S., RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M., RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V., RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J., RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F., RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F., RA Waterston R., Hood L., Weissenbach J.; RT "The DNA sequence and analysis of human chromosome 14."; RL Nature 421:601-607(2003). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT RP TRP-157. RC TISSUE=Brain; 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 project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(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., Buerckstuemmer T., RA 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 INTERACTION WITH PRKN. RX PubMed=24270810; DOI=10.1038/nature12748; RA Hasson S.A., Kane L.A., Yamano K., Huang C.H., Sliter D.A., Buehler E., RA Wang C., Heman-Ackah S.M., Hessa T., Guha R., Martin S.E., Youle R.J.; RT "High-content genome-wide RNAi screens identify regulators of parkin RT upstream of mitophagy."; RL Nature 504:291-295(2013). RN [7] RP STRUCTURE BY NMR OF 275-350, X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF RP 341-447 IN COMPLEX WITH HSPA1, DOMAIN BAG, FUNCTION, AND SUBUNIT. RX PubMed=20223214; DOI=10.1016/j.str.2010.01.004; RA Arakawa A., Handa N., Ohsawa N., Shida M., Kigawa T., Hayashi F., RA Shirouzu M., Yokoyama S.; RT "The C-terminal BAG domain of BAG5 induces conformational changes of the RT Hsp70 nucleotide-binding domain for ADP-ATP exchange."; RL Structure 18:309-319(2010). RN [8] RP VARIANTS CMD2F 197-ARG--TYR-447 DEL AND 390-ARG--TYR-447 DEL, RP CHARACTERIZATION OF VARIANT CMD2F 390-ARG--TYR-447 DEL, INVOLVEMENT IN RP CMD2F, INTERACTION WITH HSPA8 AND JPH2, AND TISSUE SPECIFICITY. RX PubMed=35044787; DOI=10.1126/scitranslmed.abf3274; RA Hakui H., Kioka H., Miyashita Y., Nishimura S., Matsuoka K., Kato H., RA Tsukamoto O., Kuramoto Y., Takuwa A., Takahashi Y., Saito S., Ohta K., RA Asanuma H., Fu H.Y., Shinomiya H., Yamada N., Ohtani T., Sawa Y., RA Kitakaze M., Takashima S., Sakata Y., Asano Y.; RT "Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated RT cardiomyopathy requiring heart transplantation."; RL Sci. Transl. Med. 14:eabf3274-eabf3274(2022). CC -!- FUNCTION: Co-chaperone for HSP/HSP70 proteins. It functions as a CC nucleotide-exchange factor promoting the release of ADP from HSP70, CC thereby activating HSP70-mediated protein refolding (PubMed:20223214). CC Has an essential role in maintaining proteostasis at junctional CC membrane complexes (JMC), where it may function as a scaffold between CC the HSPA8 chaperone and JMC proteins enabling correct, HSPA8-dependent CC JMC protein folding (By similarity). Inhibits both auto-ubiquitination CC of PRKN and ubiquitination of target proteins by PRKN (By similarity). CC {ECO:0000250|UniProtKB:Q5QJC9, ECO:0000250|UniProtKB:Q8CI32, CC ECO:0000269|PubMed:20223214}. CC -!- SUBUNIT: Binds to the ATPase domain of HSP/HSP70 chaperones. Binds CC PRKN. Interacts with HSPA8 and JPH2 (PubMed:35044787). CC {ECO:0000269|PubMed:20223214, ECO:0000269|PubMed:35044787}. CC -!- INTERACTION: CC Q9UL15; Q8N9N5: BANP; NbExp=3; IntAct=EBI-356517, EBI-744695; CC Q9UL15; Q96GN5: CDCA7L; NbExp=3; IntAct=EBI-356517, EBI-5278764; CC Q9UL15; P17661: DES; NbExp=3; IntAct=EBI-356517, EBI-1055572; CC Q9UL15; Q12805: EFEMP1; NbExp=3; IntAct=EBI-356517, EBI-536772; CC Q9UL15; Q9BPY3: FAM118B; NbExp=3; IntAct=EBI-356517, EBI-726822; CC Q9UL15; Q9NYA3: GOLGA6A; NbExp=3; IntAct=EBI-356517, EBI-11163335; CC Q9UL15; P08107: HSPA1B; NbExp=6; IntAct=EBI-356517, EBI-629985; CC Q9UL15; Q8N6L0: KASH5; NbExp=6; IntAct=EBI-356517, EBI-749265; CC Q9UL15; Q6L8H1: KRTAP5-4; NbExp=3; IntAct=EBI-356517, EBI-11963072; CC Q9UL15; Q5TA81: LCE2C; NbExp=3; IntAct=EBI-356517, EBI-11973993; CC Q9UL15; Q38SD2: LRRK1; NbExp=3; IntAct=EBI-356517, EBI-1050422; CC Q9UL15; Q5S007: LRRK2; NbExp=12; IntAct=EBI-356517, EBI-5323863; CC Q9UL15; Q9Y6D9: MAD1L1; NbExp=7; IntAct=EBI-356517, EBI-742610; CC Q9UL15; Q9NVV9: THAP1; NbExp=7; IntAct=EBI-356517, EBI-741515; CC Q9UL15; O60784-2: TOM1; NbExp=3; IntAct=EBI-356517, EBI-12117154; CC Q9UL15; P14373: TRIM27; NbExp=6; IntAct=EBI-356517, EBI-719493; CC Q9UL15; Q53FC7; NbExp=2; IntAct=EBI-356517, EBI-9356749; CC -!- SUBCELLULAR LOCATION: Note=In cardiomyocytes, localized at specialized CC membrane contact sites between T-tubules and the sarcoplasmic CC reticulum, known as junctional membrane complexes. CC {ECO:0000250|UniProtKB:Q8CI32}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q9UL15-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9UL15-2; Sequence=VSP_037996; CC -!- TISSUE SPECIFICITY: Expressed in the heart. CC {ECO:0000269|PubMed:35044787}. CC -!- DOMAIN: The fifth BAG domain is responsible for the interaction with CC HSP70 nucleotide-binding domain. {ECO:0000269|PubMed:20223214}. CC -!- DISEASE: Cardiomyopathy, dilated, 2F (CMD2F) [MIM:619747]: A form of CC dilated cardiomyopathy, a disorder characterized by ventricular CC dilation and impaired systolic function, resulting in congestive heart CC failure and arrhythmia. Patients are at risk of premature death. CMD2F CC is an autosomal recessive, early-onset form. CC {ECO:0000269|PubMed:35044787}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SEQUENCE CAUTION: CC Sequence=BAA74896.1; Type=Erroneous initiation; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF095195; AAD16124.2; -; mRNA. DR EMBL; AB020680; BAA74896.1; ALT_INIT; mRNA. DR EMBL; AL139300; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC044216; AAH44216.2; -; mRNA. DR EMBL; BC050551; AAH50551.1; -; mRNA. DR CCDS; CCDS9982.1; -. [Q9UL15-1] DR RefSeq; NP_001015048.1; NM_001015048.2. [Q9UL15-1] DR RefSeq; NP_001015049.1; NM_001015049.2. [Q9UL15-1] DR RefSeq; NP_004864.1; NM_004873.3. [Q9UL15-1] DR PDB; 2D9D; NMR; -; A=275-350. DR PDB; 3A8Y; X-ray; 2.30 A; C/D=341-447. DR PDBsum; 2D9D; -. DR PDBsum; 3A8Y; -. DR AlphaFoldDB; Q9UL15; -. DR SMR; Q9UL15; -. DR BioGRID; 114905; 372. DR CORUM; Q9UL15; -. DR DIP; DIP-53428N; -. DR IntAct; Q9UL15; 99. DR MINT; Q9UL15; -. DR STRING; 9606.ENSP00000338814; -. DR GlyGen; Q9UL15; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q9UL15; -. DR MetOSite; Q9UL15; -. DR PhosphoSitePlus; Q9UL15; -. DR BioMuta; BAG5; -. DR DMDM; 12643895; -. DR EPD; Q9UL15; -. DR jPOST; Q9UL15; -. DR MassIVE; Q9UL15; -. DR MaxQB; Q9UL15; -. DR PaxDb; 9606-ENSP00000338814; -. DR PeptideAtlas; Q9UL15; -. DR ProteomicsDB; 84927; -. [Q9UL15-1] DR ProteomicsDB; 84928; -. [Q9UL15-2] DR Pumba; Q9UL15; -. DR Antibodypedia; 36; 624 antibodies from 36 providers. DR DNASU; 9529; -. DR Ensembl; ENST00000299204.6; ENSP00000299204.4; ENSG00000166170.12. [Q9UL15-1] DR Ensembl; ENST00000337322.5; ENSP00000338814.5; ENSG00000166170.12. [Q9UL15-1] DR Ensembl; ENST00000445922.2; ENSP00000391713.2; ENSG00000166170.12. [Q9UL15-1] DR GeneID; 9529; -. DR KEGG; hsa:9529; -. DR MANE-Select; ENST00000299204.6; ENSP00000299204.4; NM_001015048.3; NP_001015048.1. DR UCSC; uc001ynh.3; human. [Q9UL15-1] DR AGR; HGNC:941; -. DR CTD; 9529; -. DR DisGeNET; 9529; -. DR GeneCards; BAG5; -. DR HGNC; HGNC:941; BAG5. DR HPA; ENSG00000166170; Tissue enriched (testis). DR MalaCards; BAG5; -. DR MIM; 603885; gene. DR MIM; 619747; phenotype. DR neXtProt; NX_Q9UL15; -. DR OpenTargets; ENSG00000166170; -. DR Orphanet; 154; Familial isolated dilated cardiomyopathy. DR PharmGKB; PA25241; -. DR VEuPathDB; HostDB:ENSG00000166170; -. DR eggNOG; KOG4361; Eukaryota. DR GeneTree; ENSGT00940000158888; -. DR HOGENOM; CLU_579940_0_0_1; -. DR InParanoid; Q9UL15; -. DR OMA; MGNQHPA; -. DR OrthoDB; 4022185at2759; -. DR PhylomeDB; Q9UL15; -. DR TreeFam; TF102014; -. DR PathwayCommons; Q9UL15; -. DR Reactome; R-HSA-3371453; Regulation of HSF1-mediated heat shock response. DR SignaLink; Q9UL15; -. DR SIGNOR; Q9UL15; -. DR BioGRID-ORCS; 9529; 4 hits in 1153 CRISPR screens. DR EvolutionaryTrace; Q9UL15; -. DR GeneWiki; BAG5; -. DR GenomeRNAi; 9529; -. DR Pharos; Q9UL15; Tbio. DR PRO; PR:Q9UL15; -. DR Proteomes; UP000005640; Chromosome 14. DR RNAct; Q9UL15; Protein. DR Bgee; ENSG00000166170; Expressed in sperm and 207 other cell types or tissues. DR ExpressionAtlas; Q9UL15; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; IDA:ParkinsonsUK-UCL. DR GO; GO:0016234; C:inclusion body; IDA:BHF-UCL. DR GO; GO:0030314; C:junctional membrane complex; ISS:UniProtKB. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IDA:ParkinsonsUK-UCL. DR GO; GO:0005634; C:nucleus; IDA:ParkinsonsUK-UCL. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:BHF-UCL. DR GO; GO:0000774; F:adenyl-nucleotide exchange factor activity; IBA:GO_Central. DR GO; GO:0019901; F:protein kinase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0051087; F:protein-folding chaperone binding; IPI:BHF-UCL. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0007030; P:Golgi organization; IMP:ParkinsonsUK-UCL. DR GO; GO:0010977; P:negative regulation of neuron projection development; IDA:ParkinsonsUK-UCL. DR GO; GO:1902176; P:negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:0032435; P:negative regulation of proteasomal ubiquitin-dependent protein catabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0061084; P:negative regulation of protein refolding; ISS:BHF-UCL. DR GO; GO:0031397; P:negative regulation of protein ubiquitination; IDA:ARUK-UCL. DR GO; GO:0051444; P:negative regulation of ubiquitin-protein transferase activity; ISS:BHF-UCL. DR GO; GO:0006457; P:protein folding; TAS:ProtInc. DR GO; GO:0050821; P:protein stabilization; IDA:ARUK-UCL. DR GO; GO:0090083; P:regulation of inclusion body assembly; IMP:BHF-UCL. DR GO; GO:0051438; P:regulation of ubiquitin-protein transferase activity; TAS:ParkinsonsUK-UCL. DR Gene3D; 1.20.58.120; BAG domain; 5. DR InterPro; IPR039773; BAG_chaperone_regulator. DR InterPro; IPR036533; BAG_dom_sf. DR InterPro; IPR003103; BAG_domain. DR PANTHER; PTHR12329:SF2; BAG FAMILY MOLECULAR CHAPERONE REGULATOR 5; 1. DR PANTHER; PTHR12329; BCL2-ASSOCIATED ATHANOGENE; 1. DR Pfam; PF02179; BAG; 4. DR SMART; SM00264; BAG; 4. DR SUPFAM; SSF63491; BAG domain; 4. DR PROSITE; PS51035; BAG; 4. DR Genevisible; Q9UL15; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cardiomyopathy; Chaperone; KW Disease variant; Reference proteome; Repeat. FT CHAIN 1..447 FT /note="BAG family molecular chaperone regulator 5" FT /id="PRO_0000088872" FT DOMAIN 9..86 FT /note="BAG 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00369" FT DOMAIN 95..167 FT /note="BAG 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00369" FT DOMAIN 182..260 FT /note="BAG 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00369" FT DOMAIN 275..350 FT /note="BAG 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00369" FT DOMAIN 365..442 FT /note="BAG 5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00369" FT VAR_SEQ 1 FT /note="M -> MRFHWLPTLSEPFDRNQELETCIRPLWTPSGSACETEHNKSM (in FT isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_037996" FT VARIANT 157 FT /note="C -> W (in dbSNP:rs17854644)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_058712" FT VARIANT 197..447 FT /note="Missing (in CMD2F)" FT /evidence="ECO:0000269|PubMed:35044787" FT /id="VAR_086932" FT VARIANT 390..447 FT /note="Missing (in CMD2F; loss of interaction with HSPA8)" FT /evidence="ECO:0000269|PubMed:35044787" FT /id="VAR_086933" FT HELIX 277..295 FT /evidence="ECO:0007829|PDB:2D9D" FT TURN 299..301 FT /evidence="ECO:0007829|PDB:2D9D" FT HELIX 302..317 FT /evidence="ECO:0007829|PDB:2D9D" FT HELIX 318..320 FT /evidence="ECO:0007829|PDB:2D9D" FT HELIX 326..350 FT /evidence="ECO:0007829|PDB:2D9D" FT TURN 356..358 FT /evidence="ECO:0007829|PDB:3A8Y" FT HELIX 364..384 FT /evidence="ECO:0007829|PDB:3A8Y" FT HELIX 393..410 FT /evidence="ECO:0007829|PDB:3A8Y" FT HELIX 418..442 FT /evidence="ECO:0007829|PDB:3A8Y" SQ SEQUENCE 447 AA; 51200 MW; 0D3F7EA6B612C1F5 CRC64; MDMGNQHPSI SRLQEIQKEV KSVEQQVIGF SGLSDDKNYK KLERILTKQL FEIDSVDTEG KGDIQQARKR AAQETERLLK ELEQNANHPH RIEIQNIFEE AQSLVREKIV PFYNGGNCVT DEFEEGIQDI ILRLTHVKTG GKISLRKARY HTLTKICAVQ EIIEDCMKKQ PSLPLSEDAH PSVAKINFVM CEVNKARGVL IALLMGVNNN ETCRHLSCVL SGLIADLDAL DVCGRTEIRN YRREVVEDIN KLLKYLDLEE EADTTKAFDL RQNHSILKIE KVLKRMREIK NELLQAQNPS ELYLSSKTEL QGLIGQLDEV SLEKNPCIRE ARRRAVIEVQ TLITYIDLKE ALEKRKLFAC EEHPSHKAVW NVLGNLSEIQ GEVLSFDGNR TDKNYIRLEE LLTKQLLALD AVDPQGEEKC KAARKQAVRL AQNILSYLDL KSDEWEY //