Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4Z0S2U)

• DOT Name: Large proline-rich protein BAG6 (BAG6)
• Synonyms: BAG family molecular chaperone regulator 6; BCL2-associated athanogene 6; BAG-6; HLA-B-associated transcript 3; Protein G3; Protein Scythe
• Gene Name: BAG6
• Related Disease:
  Classic Hodgkin lymphoma
  Neoplasm
  Aural atresia, congenital
  B-cell lymphoma
  Endometriosis
  Epilepsy
  Epstein barr virus infection
  High blood pressure
  Knee osteoarthritis
  Lung cancer
  Lung carcinoma
  Multiple sclerosis
  Non-small-cell lung cancer
  Osteoarthritis
  Osteosarcoma
  Plasma cell myeloma
  Prion disease
  Rheumatoid arthritis
  Schwartz-Jampel syndrome
  Stevens-Johnson syndrome
  Toxic epidermal necrolysis
  Type-1 diabetes
  Advanced cancer
  Gastrointestinal stromal tumour
  Hepatocellular carcinoma
  Lung neoplasm
  Small lymphocytic lymphoma
  Systemic lupus erythematosus
  Tuberculosis
  Psoriatic arthritis
• UniProt ID: BAG6_HUMAN
• PDB ID: 1WX9; 2N9P; 4DWF; 4EEW; 4WWR; 4X86; 6AU8; 7RU9; 7RUA; 7RUC
• Pfam ID: PF12057 ; PF20960 ; PF00240
• Sequence:
  MEPNDSTSTAVEEPDSLEVLVKTLDSQTRTFIVGAQMNVKEFKEHIAASVSIPSEKQRLI
  YQGRVLQDDKKLQEYNVGGKVIHLVERAPPQTHLPSGASSGTGSASATHGGGSPPGTRGP
  GASVHDRNANSYVMVGTFNLPSDGSAVDVHINMEQAPIQSEPRVRLVMAQHMIRDIQTLL
  SRMETLPYLQCRGGPQPQHSQPPPQPPAVTPEPVALSSQTSEPVESEAPPREPMEAEEVE
  ERAPAQNPELTPGPAPAGPTPAPETNAPNHPSPAEYVEVLQELQRLESRLQPFLQRYYEV
  LGAAATTDYNNNHEGREEDQRLINLVGESLRLLGNTFVALSDLRCNLACTPPRHLHVVRP
  MSHYTTPMVLQQAAIPIQINVGTTVTMTGNGTRPPPTPNAEAPPPGPGQASSVAPSSTNV
  ESSAEGAPPPGPAPPPATSHPRVIRISHQSVEPVVMMHMNIQDSGTQPGGVPSAPTGPLG
  PPGHGQTLGQQVPGFPTAPTRVVIARPTPPQARPSHPGGPPVSGTLQGAGLGTNASLAQM
  VSGLVGQLLMQPVLVAQGTPGMAPPPAPATASASAGTTNTATTAGPAPGGPAQPPPTPQP
  SMADLQFSQLLGNLLGPAGPGAGGSGVASPTITVAMPGVPAFLQGMTDFLQATQTAPPPP
  PPPPPPPPAPEQQTMPPPGSPSGGAGSPGGLGLESLSPEFFTSVVQGVLSSLLGSLGARA
  GSSESIAAFIQRLSGSSNIFEPGADGALGFFGALLSLLCQNFSMVDVVMLLHGHFQPLQR
  LQPQLRSFFHQHYLGGQEPTPSNIRMATHTLITGLEEYVRESFSLVQVQPGVDIIRTNLE
  FLQEQFNSIAAHVLHCTDSGFGARLLELCNQGLFECLALNLHCLGGQQMELAAVINGRIR
  RMSRGVNPSLVSWLTTMMGLRLQVVLEHMPVGPDAILRYVRRVGDPPQPLPEEPMEVQGA
  ERASPEPQRENASPAPGTTAEEAMSRGPPPAPEGGSRDEQDGASAETEPWAAAVPPEWVP
  IIQQDIQSQRKVKPQPPLSDAYLSGMPAKRRKTMQGEGPQLLLSEAVSRAAKAAGARPLT
  SPESLSRDLEAPEVQESYRQQLRSDIQKRLQEDPNYSPQRFPNAQRAFADDP
• Function: ATP-independent molecular chaperone preventing the aggregation of misfolded and hydrophobic patches-containing proteins. Functions as part of a cytosolic protein quality control complex, the BAG6/BAT3 complex, which maintains these client proteins in a soluble state and participates in their proper delivery to the endoplasmic reticulum or alternatively can promote their sorting to the proteasome where they undergo degradation. The BAG6/BAT3 complex is involved in the post-translational delivery of tail-anchored/type II transmembrane proteins to the endoplasmic reticulum membrane. Recruited to ribosomes, it interacts with the transmembrane region of newly synthesized tail-anchored proteins and together with SGTA and ASNA1 mediates their delivery to the endoplasmic reticulum. Client proteins that cannot be properly delivered to the endoplasmic reticulum are ubiquitinated by RNF126, an E3 ubiquitin-protein ligase associated with BAG6 and are sorted to the proteasome. SGTA which prevents the recruitment of RNF126 to BAG6 may negatively regulate the ubiquitination and the proteasomal degradation of client proteins. Similarly, the BAG6/BAT3 complex also functions as a sorting platform for proteins of the secretory pathway that are mislocalized to the cytosol either delivering them to the proteasome for degradation or to the endoplasmic reticulum. The BAG6/BAT3 complex also plays a role in the endoplasmic reticulum-associated degradation (ERAD), a quality control mechanism that eliminates unwanted proteins of the endoplasmic reticulum through their retrotranslocation to the cytosol and their targeting to the proteasome. It maintains these retrotranslocated proteins in an unfolded yet soluble state condition in the cytosol to ensure their proper delivery to the proteasome. BAG6 is also required for selective ubiquitin-mediated degradation of defective nascent chain polypeptides by the proteasome. In this context, it may participate in the production of antigenic peptides and play a role in antigen presentation in immune response. BAG6 is also involved in endoplasmic reticulum stress-induced pre-emptive quality control, a mechanism that selectively attenuates the translocation of newly synthesized proteins into the endoplasmic reticulum and reroutes them to the cytosol for proteasomal degradation. BAG6 may ensure the proper degradation of these proteins and thereby protects the endoplasmic reticulum from protein overload upon stress. By inhibiting the polyubiquitination and subsequent proteasomal degradation of HSPA2 it may also play a role in the assembly of the synaptonemal complex during spermatogenesis. Also positively regulates apoptosis by interacting with and stabilizing the proapoptotic factor AIFM1. By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway ; Involved in DNA damage-induced apoptosis: following DNA damage, accumulates in the nucleus and forms a complex with p300/EP300, enhancing p300/EP300-mediated p53/TP53 acetylation leading to increase p53/TP53 transcriptional activity. When nuclear, may also act as a component of some chromatin regulator complex that regulates histone 3 'Lys-4' dimethylation (H3K4me2) ; Released extracellularly via exosomes, it is a ligand of the natural killer/NK cells receptor NCR3 and stimulates NK cells cytotoxicity. It may thereby trigger NK cells cytotoxicity against neighboring tumor cells and immature myeloid dendritic cells (DC); Mediates ricin-induced apoptosis.
• Tissue Specificity: Expressed by immature dendritic cells (at protein level).
• KEGG Pathway: Protein export (hsa03060)
• Reactome Pathway: Insertion of tail-anchored proteins into the endoplasmic reticulum membrane (R-HSA-9609523)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Classic Hodgkin lymphoma	DISV1LU6	Definitive	Genetic Variation	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[2]
Aural atresia, congenital	DISCP7UV	Strong	Genetic Variation	[3]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[4]
Endometriosis	DISX1AG8	Strong	Altered Expression	[5]
Epilepsy	DISBB28L	Strong	Genetic Variation	[6]
Epstein barr virus infection	DISOO0WT	Strong	Genetic Variation	[7]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[8]
Knee osteoarthritis	DISLSNBJ	Strong	Genetic Variation	[9]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[10]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[10]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[11]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[12]
Osteoarthritis	DIS05URM	Strong	Genetic Variation	[9]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[13]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[14]
Prion disease	DISOUMB0	Strong	Altered Expression	[15]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[16]
Schwartz-Jampel syndrome	DIS3HCR8	Strong	Biomarker	[6]
Stevens-Johnson syndrome	DISZG4YX	Strong	Biomarker	[6]
Toxic epidermal necrolysis	DISIWPFR	Strong	Genetic Variation	[6]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[17]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[18]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Altered Expression	[19]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[20]
Lung neoplasm	DISVARNB	moderate	Biomarker	[18]
Small lymphocytic lymphoma	DIS30POX	moderate	Biomarker	[21]
Systemic lupus erythematosus	DISI1SZ7	moderate	Genetic Variation	[22]
Tuberculosis	DIS2YIMD	Disputed	Biomarker	[23]
Psoriatic arthritis	DISLWTG2	Limited	Genetic Variation	[24]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Large proline-rich protein BAG6 (BAG6) affects the response to substance of Methotrexate.	[35]

9 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Large proline-rich protein BAG6 (BAG6).	[25]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Large proline-rich protein BAG6 (BAG6).	[26]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Large proline-rich protein BAG6 (BAG6).	[27]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Large proline-rich protein BAG6 (BAG6).	[28]
Selenium	DM25CGV	Approved	Selenium increases the expression of Large proline-rich protein BAG6 (BAG6).	[29]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Large proline-rich protein BAG6 (BAG6).	[30]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Large proline-rich protein BAG6 (BAG6).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Large proline-rich protein BAG6 (BAG6).	[33]
Staurosporine	DM0E9BR	Investigative	Staurosporine decreases the expression of Large proline-rich protein BAG6 (BAG6).	[34]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Large proline-rich protein BAG6 (BAG6).	[31]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Large proline-rich protein BAG6 (BAG6).	[32]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Large proline-rich protein BAG6 (BAG6).	[32]

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