Large proline-rich protein BAG6 (BAG6)
The protein contains 1132 amino acids for an estimated molecular weight of 119409 Da.
ATP-independent molecular chaperone preventing the aggregation of misfolded and hydrophobic patches-containing proteins (PubMed:21636303). 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 (PubMed:20516149, PubMed:21636303, PubMed:21743475, PubMed:28104892). 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 (PubMed:20516149, PubMed:20676083, PubMed:28104892, PubMed:25535373). 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 (PubMed:24981174, PubMed:28104892, PubMed:27193484). SGTA which prevents the recruitment of RNF126 to BAG6 may negatively regulate the ubiquitination and the proteasomal degradation of client proteins (PubMed:23129660, PubMed:25179605, PubMed:27193484). Similarly, the BAG6/BAT3 complex also functions as a sorting platform for proteins of the secretory pathway tha (updated: June 17, 2020)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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| Variant | Description |
|---|---|
| dbSNP:rs1052486 | |
| dbSNP:rs11548856 |
Biological Process
Apoptotic process
Brain development
Cell differentiation
Chromatin organization
Covalent chromatin modification
Embryo development
Endoplasmic reticulum stress-induced pre-emptive quality control
ER-associated misfolded protein catabolic process
Immune response-activating cell surface receptor signaling pathway
Immune system process
Internal peptidyl-lysine acetylation
Intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator
Intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress
Kidney development
Lung development
Maintenance of unfolded protein involved in ERAD pathway
Natural killer cell activation
Negative regulation of apoptotic process
Negative regulation of proteasomal ubiquitin-dependent protein catabolic process
Negative regulation of proteolysis
Positive regulation of ERAD pathway
Proteasomal protein catabolic process
Protein localization to cytosolic proteasome complex involved in ERAD pathway
Protein stabilization
Regulation of cell population proliferation
Regulation of embryonic development
Spermatogenesis
Synaptonemal complex assembly
Tail-anchored membrane protein insertion into ER membrane
Transport
Ubiquitin-dependent ERAD pathway
Ubiquitin-dependent protein catabolic process
The reference OMIM entry for this protein is 142590
Bcl2-associated athanogene 6; bag6
Scythe, xenopus, homolog of
Hla-b-associated transcript 3; bat3
D6s52e
CLONING
By chromosome walking with overlapping cosmids, Spies et al. (1989) isolated a 435-kb DNA segment that was centromeric to HLA-B (142830) in the human major histocompatibility complex. The presence of additional genes was suggested by a large cluster of CpG islands. With cosmid probes, 5 distinct transcripts, including BAT3, were detected in RNA samples from a variety of cell lines, and the corresponding cDNA clones were isolated. From cDNA clones, Banerji et al. (1990) determined the complete sequences of the closely linked BAT2 (142580) and BAT3 genes. The putative proteins are 228 and 110 kD, respectively. BAT3 contains an N-terminal ubiquitin-like domain, and both BAT2 and BAT3 are rich in proline and include short tracts of polyproline, polyglycine, and charged amino acids.GENE FUNCTION
Sasaki et al. (2007) showed that depletion of BAT3 from human and mouse cells impaired p53 (TP53; 191170)-mediated transactivation of its target genes Puma (BBC3; 605854) and p21 (CDKN1A; 116899). Although DNA damage-induced phosphorylation, stabilization, and nuclear accumulation of p53 were not significantly affected by BAT3 depletion, p53 acetylation was almost completely abolished. BAT3 formed a complex with p300 (EP300; 602700), and an increased amount of BAT3 enhanced recruitment of p53 to p300 and facilitated subsequent p53 acetylation. In contrast, Bat3-depleted cells showed reduced p53-p300 complex formation and decreased p53 acetylation. Thymocytes from Bat3-deficient mice exhibited reduced p53-mediated induction of Puma and p21 and were resistant to DNA damage-induced apoptosis in vivo. Sasaki et al. (2007) concluded that BAT3 is an essential regulator of p53-mediated responses to genotoxic stress, and that BAT3 controls DNA damage-induced acetylation of p53. Mariappan et al. (2010) identified a conserved 3-protein complex composed of BAT3, TRC35 (612056), and UBL4A (312070) that facilitates tail-anchored protein capture by TRC40 (601913). This BAT3 complex is recruited to ribosomes synthesizing membrane proteins, interacts with the transmembrane domains of newly released tail-anchored proteins, and transfers them to TRC40 for targeting. Depletion of the BAT3 complex allows non-TRC40 factors to compete for tail-anchored proteins, explaining their mislocalization in the analogous yeast deletion strains. Thus, the BAT3 complex acts as a TMD-selective chaperone that effectively channels tail-anchored proteins to the TRC40 insertion pathway. Hessa et al. (2011) reconstituted mislocalized protein degradation in vitro to identify factors involved in the pathway and found that nascent membrane proteins tethered to ribosomes are not substrates for ubiquitination unless they are released into the cytosol. Their inappropriate release results in capture by the BAG6 complex, a ribosome-associating chaperone. BAG6 complex-mediated capture depends on the presence of unprocessed or noninserted hydrophobic domains that distinguish mislocalized proteins from potential cytosolic proteins. A subset of these BAG6 complex 'clients' are transferred to TRC40 for insertion into the membrane, whereas the remainder are rapidly ubiquitinated. Depletion of the BAG6 complex selectively impairs the efficient ubiquitination of mislocalized proteins. Thus, Hessa et al. (2011) concluded that by its presence on ribosomes that are synthesizing nascent membrane proteins, the BAG6 complex links targeting and ubiquitination pathways. The authors ... More on the omim web site
June 29, 2020: Protein entry updated
Automatic update: Entry updated from uniprot information.
May 12, 2019: Protein entry updated
Automatic update: model status changed
Nov. 17, 2018: Protein entry updated
Automatic update: model status changed
July 2, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
Oct. 27, 2017: Protein entry updated
Automatic update: model status changed
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 142590 was added.
Jan. 24, 2016: Protein entry updated
Automatic update: model status changed