| Structural highlights
Function
[UBL4A_HUMAN] Component of the BAT3 complex, a multiprotein complex involved in the post-translational delivery of tail-anchored (TA) membrane proteins to the endoplasmic reticulum membrane. TA membrane proteins, also named type II transmembrane proteins, contain a single C-terminal transmembrane region. The complex acts by facilitating TA proteins capture by ASNA1/TRC40: it is recruited to ribosomes synthesizing membrane proteins, interacts with the transmembrane region of newly released TA proteins, and transfers them to ASNA1/TRC40 for targeting.[1] [BAG6_HUMAN] Chaperone that plays a key role in various processes such as apoptosis, insertion of tail-anchored (TA) membrane proteins to the endoplasmic reticulum membrane and regulation of chromatin. Acts in part by regulating stability of proteins and their degradation by the proteasome. Participates in endoplasmic reticulum stress-induced apoptosis via its interaction with AIFM1/AIF by regulating AIFM1/AIF stability and preventing its degradation. Also required during spermatogenesis for synaptonemal complex assembly via its interaction with HSPA2, by inhibiting polyubiquitination and subsequent proteasomal degradation of HSPA2. Required for selective ubiquitin-mediated degradation of defective nascent chain polypeptides by the proteasome. In this context, may play a role in immuno-proteasomes to generate antigenic peptides via targeted degradation, thereby playing a role in antigen presentation in immune response. Key component of the BAG6/BAT3 complex, a cytosolic multiprotein complex involved in the post-translational delivery of tail-anchored (TA) membrane proteins to the endoplasmic reticulum membrane. TA membrane proteins, also named type II transmembrane proteins, contain a single C-terminal transmembrane region. BAG6/BAT3 acts by facilitating TA membrane proteins capture by ASNA1/TRC40: it is recruited to ribosomes synthesizing membrane proteins, interacts with the transmembrane region of newly released TA proteins and transfers them to ASNA1/TRC40 for targeting to the endoplasmic reticulum membrane.[2] [3] [4] [5] [6] [7] [8] 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).[9] [10] [11] [12] [13] [14] [15] Can be released from tumor and dendritic cells in membrane vesicles or exosomes, and engage NCR3 thereby promoting natural killer cell (NK) activation and cytotoxicity.[16] [17] [18] [19] [20] [21] [22]
Publication Abstract from PubMed
BCL2-associated athanogene cochaperone 6 (Bag6) plays a central role in cellular homeostasis in a diverse array of processes and is part of the heterotrimeric Bag6 complex, which also includes ubiquitin-like 4A (Ubl4A) and transmembrane domain recognition complex 35 (TRC35). This complex recently has been shown to be important in the TRC pathway, the mislocalized protein degradation pathway, and the endoplasmic reticulum-associated degradation pathway. Here we define the architecture of the Bag6 complex, demonstrating that both TRC35 and Ubl4A have distinct C-terminal binding sites on Bag6 defining a minimal Bag6 complex. A crystal structure of the Bag6-Ubl4A dimer demonstrates that Bag6-BAG is not a canonical BAG domain, and this finding is substantiated biochemically. Remarkably, the minimal Bag6 complex defined here facilitates tail-anchored substrate transfer from small glutamine-rich tetratricopeptide repeat-containing protein alpha to TRC40. These findings provide structural insight into the complex network of proteins coordinated by Bag6.
Bag6 complex contains a minimal tail-anchor-targeting module and a mock BAG domain.,Mock J, Chartron JW, Zaslaver M, Xu Y, Ye Y, Clemons WM Jr Proc Natl Acad Sci U S A. 2014 Dec 22. pii: 201402745. PMID:25535373[23]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Mariappan M, Li X, Stefanovic S, Sharma A, Mateja A, Keenan RJ, Hegde RS. A ribosome-associating factor chaperones tail-anchored membrane proteins. Nature. 2010 Aug 26;466(7310):1120-4. doi: 10.1038/nature09296. Epub 2010 Aug 1. PMID:20676083 doi:http://dx.doi.org/10.1038/nature09296
- ↑ Wu YH, Shih SF, Lin JY. Ricin triggers apoptotic morphological changes through caspase-3 cleavage of BAT3. J Biol Chem. 2004 Apr 30;279(18):19264-75. Epub 2004 Feb 11. PMID:14960581 doi:http://dx.doi.org/10.1074/jbc.M307049200
- ↑ Sasaki T, Gan EC, Wakeham A, Kornbluth S, Mak TW, Okada H. HLA-B-associated transcript 3 (Bat3)/Scythe is essential for p300-mediated acetylation of p53. Genes Dev. 2007 Apr 1;21(7):848-61. PMID:17403783 doi:http://dx.doi.org/10.1101/gad.1534107
- ↑ Pogge von Strandmann E, Simhadri VR, von Tresckow B, Sasse S, Reiners KS, Hansen HP, Rothe A, Boll B, Simhadri VL, Borchmann P, McKinnon PJ, Hallek M, Engert A. Human leukocyte antigen-B-associated transcript 3 is released from tumor cells and engages the NKp30 receptor on natural killer cells. Immunity. 2007 Dec;27(6):965-74. Epub 2007 Dec 6. PMID:18055229 doi:http://dx.doi.org/10.1016/j.immuni.2007.10.010
- ↑ Nguyen P, Bar-Sela G, Sun L, Bisht KS, Cui H, Kohn E, Feinberg AP, Gius D. BAT3 and SET1A form a complex with CTCFL/BORIS to modulate H3K4 histone dimethylation and gene expression. Mol Cell Biol. 2008 Nov;28(21):6720-9. Epub 2008 Sep 2. PMID:18765639 doi:http://dx.doi.org/MCB.00568-08
- ↑ Simhadri VR, Reiners KS, Hansen HP, Topolar D, Simhadri VL, Nohroudi K, Kufer TA, Engert A, Pogge von Strandmann E. Dendritic cells release HLA-B-associated transcript-3 positive exosomes to regulate natural killer function. PLoS One. 2008;3(10):e3377. doi: 10.1371/journal.pone.0003377. Epub 2008 Oct 13. PMID:18852879 doi:10.1371/journal.pone.0003377
- ↑ Leznicki P, Clancy A, Schwappach B, High S. Bat3 promotes the membrane integration of tail-anchored proteins. J Cell Sci. 2010 Jul 1;123(Pt 13):2170-8. doi: 10.1242/jcs.066738. Epub 2010 Jun , 1. PMID:20516149 doi:http://dx.doi.org/10.1242/jcs.066738
- ↑ Mariappan M, Li X, Stefanovic S, Sharma A, Mateja A, Keenan RJ, Hegde RS. A ribosome-associating factor chaperones tail-anchored membrane proteins. Nature. 2010 Aug 26;466(7310):1120-4. doi: 10.1038/nature09296. Epub 2010 Aug 1. PMID:20676083 doi:http://dx.doi.org/10.1038/nature09296
- ↑ Wu YH, Shih SF, Lin JY. Ricin triggers apoptotic morphological changes through caspase-3 cleavage of BAT3. J Biol Chem. 2004 Apr 30;279(18):19264-75. Epub 2004 Feb 11. PMID:14960581 doi:http://dx.doi.org/10.1074/jbc.M307049200
- ↑ Sasaki T, Gan EC, Wakeham A, Kornbluth S, Mak TW, Okada H. HLA-B-associated transcript 3 (Bat3)/Scythe is essential for p300-mediated acetylation of p53. Genes Dev. 2007 Apr 1;21(7):848-61. PMID:17403783 doi:http://dx.doi.org/10.1101/gad.1534107
- ↑ Pogge von Strandmann E, Simhadri VR, von Tresckow B, Sasse S, Reiners KS, Hansen HP, Rothe A, Boll B, Simhadri VL, Borchmann P, McKinnon PJ, Hallek M, Engert A. Human leukocyte antigen-B-associated transcript 3 is released from tumor cells and engages the NKp30 receptor on natural killer cells. Immunity. 2007 Dec;27(6):965-74. Epub 2007 Dec 6. PMID:18055229 doi:http://dx.doi.org/10.1016/j.immuni.2007.10.010
- ↑ Nguyen P, Bar-Sela G, Sun L, Bisht KS, Cui H, Kohn E, Feinberg AP, Gius D. BAT3 and SET1A form a complex with CTCFL/BORIS to modulate H3K4 histone dimethylation and gene expression. Mol Cell Biol. 2008 Nov;28(21):6720-9. Epub 2008 Sep 2. PMID:18765639 doi:http://dx.doi.org/MCB.00568-08
- ↑ Simhadri VR, Reiners KS, Hansen HP, Topolar D, Simhadri VL, Nohroudi K, Kufer TA, Engert A, Pogge von Strandmann E. Dendritic cells release HLA-B-associated transcript-3 positive exosomes to regulate natural killer function. PLoS One. 2008;3(10):e3377. doi: 10.1371/journal.pone.0003377. Epub 2008 Oct 13. PMID:18852879 doi:10.1371/journal.pone.0003377
- ↑ Leznicki P, Clancy A, Schwappach B, High S. Bat3 promotes the membrane integration of tail-anchored proteins. J Cell Sci. 2010 Jul 1;123(Pt 13):2170-8. doi: 10.1242/jcs.066738. Epub 2010 Jun , 1. PMID:20516149 doi:http://dx.doi.org/10.1242/jcs.066738
- ↑ Mariappan M, Li X, Stefanovic S, Sharma A, Mateja A, Keenan RJ, Hegde RS. A ribosome-associating factor chaperones tail-anchored membrane proteins. Nature. 2010 Aug 26;466(7310):1120-4. doi: 10.1038/nature09296. Epub 2010 Aug 1. PMID:20676083 doi:http://dx.doi.org/10.1038/nature09296
- ↑ Wu YH, Shih SF, Lin JY. Ricin triggers apoptotic morphological changes through caspase-3 cleavage of BAT3. J Biol Chem. 2004 Apr 30;279(18):19264-75. Epub 2004 Feb 11. PMID:14960581 doi:http://dx.doi.org/10.1074/jbc.M307049200
- ↑ Sasaki T, Gan EC, Wakeham A, Kornbluth S, Mak TW, Okada H. HLA-B-associated transcript 3 (Bat3)/Scythe is essential for p300-mediated acetylation of p53. Genes Dev. 2007 Apr 1;21(7):848-61. PMID:17403783 doi:http://dx.doi.org/10.1101/gad.1534107
- ↑ Pogge von Strandmann E, Simhadri VR, von Tresckow B, Sasse S, Reiners KS, Hansen HP, Rothe A, Boll B, Simhadri VL, Borchmann P, McKinnon PJ, Hallek M, Engert A. Human leukocyte antigen-B-associated transcript 3 is released from tumor cells and engages the NKp30 receptor on natural killer cells. Immunity. 2007 Dec;27(6):965-74. Epub 2007 Dec 6. PMID:18055229 doi:http://dx.doi.org/10.1016/j.immuni.2007.10.010
- ↑ Nguyen P, Bar-Sela G, Sun L, Bisht KS, Cui H, Kohn E, Feinberg AP, Gius D. BAT3 and SET1A form a complex with CTCFL/BORIS to modulate H3K4 histone dimethylation and gene expression. Mol Cell Biol. 2008 Nov;28(21):6720-9. Epub 2008 Sep 2. PMID:18765639 doi:http://dx.doi.org/MCB.00568-08
- ↑ Simhadri VR, Reiners KS, Hansen HP, Topolar D, Simhadri VL, Nohroudi K, Kufer TA, Engert A, Pogge von Strandmann E. Dendritic cells release HLA-B-associated transcript-3 positive exosomes to regulate natural killer function. PLoS One. 2008;3(10):e3377. doi: 10.1371/journal.pone.0003377. Epub 2008 Oct 13. PMID:18852879 doi:10.1371/journal.pone.0003377
- ↑ Leznicki P, Clancy A, Schwappach B, High S. Bat3 promotes the membrane integration of tail-anchored proteins. J Cell Sci. 2010 Jul 1;123(Pt 13):2170-8. doi: 10.1242/jcs.066738. Epub 2010 Jun , 1. PMID:20516149 doi:http://dx.doi.org/10.1242/jcs.066738
- ↑ Mariappan M, Li X, Stefanovic S, Sharma A, Mateja A, Keenan RJ, Hegde RS. A ribosome-associating factor chaperones tail-anchored membrane proteins. Nature. 2010 Aug 26;466(7310):1120-4. doi: 10.1038/nature09296. Epub 2010 Aug 1. PMID:20676083 doi:http://dx.doi.org/10.1038/nature09296
- ↑ Mock J, Chartron JW, Zaslaver M, Xu Y, Ye Y, Clemons WM Jr. Bag6 complex contains a minimal tail-anchor-targeting module and a mock BAG domain. Proc Natl Acad Sci U S A. 2014 Dec 22. pii: 201402745. PMID:25535373 doi:http://dx.doi.org/10.1073/pnas.1402745112
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