| Structural highlights
6au8 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | |
| Gene: | GET4, C7orf20, CEE, TRC35, CGI-20 (HUMAN), BAG6, BAT3, G3 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[GET4_HUMAN] As part of a cytosolic protein quality control complex, the BAG6/BAT3 complex, maintains misfolded and hydrophobic patches-containing proteins in a soluble state and participates to their proper delivery to the endoplasmic reticulum or alternatively can promote their sorting to the proteasome where they undergo degradation (PubMed:20676083, 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:20676083, PubMed:28104892). Client proteins that cannot be properly delivered to the endoplasmic reticulum are ubiquitinated and sorted to the proteasome (PubMed:28104892). 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 (PubMed:21743475). 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 (PubMed:21636303).[1] [2] [3] [4] [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.[5] [6] [7] [8] [9] [10] [11] 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).[12] [13] [14] [15] [16] [17] [18] 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.[19] [20] [21] [22] [23] [24] [25]
Publication Abstract from PubMed
The metazoan protein BCL2-associated athanogene cochaperone 6 (Bag6) forms a hetero-trimeric complex with ubiquitin-like 4A and transmembrane domain recognition complex 35 (TRC35). This Bag6 complex is involved in tail-anchored protein targeting and various protein quality-control pathways in the cytosol as well as regulating transcription and histone methylation in the nucleus. Here we present a crystal structure of Bag6 and its cytoplasmic retention factor TRC35, revealing that TRC35 is remarkably conserved throughout the opisthokont lineage except at the C-terminal Bag6-binding groove, which evolved to accommodate Bag6, a unique metazoan factor. While TRC35 and its fungal homolog, guided entry of tail-anchored protein 4 (Get4), utilize a conserved hydrophobic patch to bind their respective partners, Bag6 wraps around TRC35 on the opposite face relative to the Get4-5 interface. We further demonstrate that TRC35 binding is critical not only for occluding the Bag6 nuclear localization sequence from karyopherin alpha to retain Bag6 in the cytosol but also for preventing TRC35 from succumbing to RNF126-mediated ubiquitylation and degradation. The results provide a mechanism for regulation of Bag6 nuclear localization and the functional integrity of the Bag6 complex in the cytosol.
Structural basis for regulation of the nucleo-cytoplasmic distribution of Bag6 by TRC35.,Mock JY, Xu Y, Ye Y, Clemons WM Jr Proc Natl Acad Sci U S A. 2017 Oct 17. pii: 201702940. doi:, 10.1073/pnas.1702940114. PMID:29042515[26]
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
- ↑ Wang Q, Liu Y, Soetandyo N, Baek K, Hegde R, Ye Y. A ubiquitin ligase-associated chaperone holdase maintains polypeptides in soluble states for proteasome degradation. Mol Cell. 2011 Jun 24;42(6):758-70. doi: 10.1016/j.molcel.2011.05.010. PMID:21636303 doi:http://dx.doi.org/10.1016/j.molcel.2011.05.010
- ↑ Hessa T, Sharma A, Mariappan M, Eshleman HD, Gutierrez E, Hegde RS. Protein targeting and degradation are coupled for elimination of mislocalized proteins. Nature. 2011 Jul 10;475(7356):394-7. doi: 10.1038/nature10181. PMID:21743475 doi:http://dx.doi.org/10.1038/nature10181
- ↑ Shao S, Rodrigo-Brenni MC, Kivlen MH, Hegde RS. Mechanistic basis for a molecular triage reaction. Science. 2017 Jan 20;355(6322):298-302. doi: 10.1126/science.aah6130. PMID:28104892 doi:http://dx.doi.org/10.1126/science.aah6130
- ↑ 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 JY, Xu Y, Ye Y, Clemons WM Jr. Structural basis for regulation of the nucleo-cytoplasmic distribution of Bag6 by TRC35. Proc Natl Acad Sci U S A. 2017 Oct 17. pii: 201702940. doi:, 10.1073/pnas.1702940114. PMID:29042515 doi:http://dx.doi.org/10.1073/pnas.1702940114
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