基因總覽
BAG6(BAG cochaperone 6)是人類蛋白質編碼基因,產物為 BAG cochaperone 6。此蛋白質具有 ubiquitin-like domain,並含有多段重複序列及多個預測為無序的區域;靠近 C 端的區域與 GET4、UBL4A 互作,以及客戶蛋白送往內質網的功能有關。BAG6 是細胞質蛋白質品質管制複合體 BAG6/BAT3 complex 的成員,也能在特定條件下進入細胞核或經胞外囊泡釋出。其作用涵蓋細胞內蛋白質處理,也包括與細胞核調控及胞外免疫訊號相關的功能。
基因異名與舊稱
異名取自 HGNC,可能包含歷史名稱;蛋白質名稱以 UniProt 註解為準。
染色體位置與基因結構
查看實際轉錄本與 exon 註解
| Transcript | Genomic coordinates | Exons |
|---|---|---|
| ENST00000676615 ★ | 31,639,028–31,652,661 | 26 |
| ENST00000375976 | 31,638,543–31,652,427 | 25 |
| ENST00000211379 | 31,638,543–31,652,747 | 25 |
| ENST00000375964 | 31,638,543–31,652,747 | 24 |
| ENST00000676571 | 31,638,543–31,652,747 | 26 |
| ENST00000362049 | 31,638,543–31,652,747 | 24 |
| ENST00000439687 | 31,638,543–31,652,747 | 23 |
| ENST00000888810 | 31,638,543–31,652,747 | 25 |
| ENST00000888811 | 31,638,543–31,652,747 | 25 |
| ENST00000888812 | 31,638,543–31,652,747 | 24 |
| ENST00000888813 | 31,638,543–31,652,734 | 25 |
| ENST00000888814 | 31,638,543–31,652,747 | 25 |
顯示 12/103 個蛋白質編碼轉錄本;canonical 優先。
帶型與著絲點依 Ensembl 座標繪製;核染色體長度以 GRCh38 第 1 號染色體為共同尺度。黃色標記表示本基因位置,細小區間加粗以利辨識;實際基因長度與 exon 見下方資料。
分子功能與生物學過程
BAG6 的主要角色是參與蛋白質品質管制。作為 BAG6/BAT3 complex 的一員,它能協助錯誤摺疊或帶有疏水區段的蛋白質避免聚集,維持其可溶狀態,並協助決定這些客戶蛋白是送往內質網,還是交由蛋白酶體降解。對於新合成的 tail-anchored/type II transmembrane proteins,複合體可在核糖體附近辨識其跨膜區段,並與 SGTA、ASNA1 協同促進其送至內質網膜。若客戶蛋白無法正確送達,與 BAG6 相關的 E3 ubiquitin-protein ligase RNF126 可促使其泛素化,進而導向蛋白酶體;SGTA 則可與 RNF126 競爭 BAG6 上的結合區域,可能降低客戶蛋白的泛素化與降解。
BAG6/BAT3 complex 也協助處理錯置於細胞質的分泌途徑蛋白,將其分流至內質網或蛋白酶體。內質網相關降解(ERAD)過程中,內質網內不需要的蛋白質會被逆向轉運至細胞質;BAG6 complex 可使這些蛋白質維持未摺疊但可溶的狀態,以利其送往蛋白酶體。BAG6 也參與新生多肽的選擇性泛素介導降解。在此脈絡下,它可能參與抗原胜肽生成及免疫反應中的抗原呈現。內質網受到壓力時,BAG6 亦參與預先品質管制,使部分新合成蛋白質減少進入內質網、改送至細胞質降解;來源指出這可能有助於避免內質網蛋白質負荷過高。
BAG6 的作用不限於細胞質蛋白質分流。DNA 受損後,BAG6 會累積於細胞核並與 p300/EP300 形成複合體,增強 p300/EP300 介導的 p53/TP53 乙醯化,提升 p53/TP53 的轉錄活性,參與 DNA 損傷誘發的細胞凋亡。它在細胞核中也可能是調控組蛋白 H3 Lys-4 二甲基化的染色質調節複合體成分。另有資料指出,BAG6 可透過抑制 HSPA2 的多聚泛素化及後續降解,可能參與精子發生時 synaptonemal complex 的組裝;它也能與促凋亡因子 AIFM1 互作並使其穩定。
BAG6 可經胞外囊泡釋出,並作為自然殺手細胞受體 NCR3 的配體,刺激自然殺手細胞的細胞毒性;它可能因此促使自然殺手細胞攻擊鄰近腫瘤細胞及未成熟髓系樹突細胞。此外,BAG6 介導 ricin 誘發的細胞凋亡,並可藉由控制 IGF1R 受體的穩態表現,間接調節 insulin-like growth factor receptor 訊號路徑。
Promoter 與基因調控
>BAG6 ENST00000676615 GRCh38 chr6:31652561-31653661 strand=-1 5′→3′ 相對 TSS:-1000 到 +100 bp;1101 bp 依轉錄本 TSS 擷取的基因組序列;TSS = 0,兩端包含,未驗證為 promoter GCAGTAAAGTACAAGTGCTCGATCTGGAGTCCTGTAGGCCTGGATTTGTCAATTCTGACACTTATGTTCG TCTAAGTGTACTCACTTAAAAAATGTTAAAAGCTCGTTAAAAGGCTTTTTAAAATAATACACAAAACCCG TAGTATATGGGCTGGCACAAGTGCTCATTAAACAGCTGCTTATTAGAACTCTTAACTAAAATATAACCAG GACCTGGGTATAAACTACGAATCCCAGAAAGGTTGGACACCCCAACAGCGATGTGTCTTTCTGGAGGACT CGCAGTTTCGCGGGGCCGAGGCCCTTGGCCCAGGGCAGGTTAAGAGAAGAGGGCACGGAGAGGCGGTAAT GCCTCCACCCCCGGCCTTCGGAAGCACGCTGGCCGGCCTTTAAATTCCCCACGGTCAGGGTCTTGTCTTT CTGTCCACTCGGACTCCATTTGCTCCCAATTCTCAAACTCGGAAGCGCCTCTTTTCTTGACAAGTCGTGC AACTTAGTAGCACGTTTACTTTTCCTAAAACGTGTCATGTCCCCTTGGCCACACACCGACGAATGTGACG CCCACAGCCCTTAAAACGCCCACCCGGCAGAACCGAAATCTAGCCCAACCAAGCAACCGAGAACAAAATT GACCAGTGCCGCCCCCAAACGCCTACTGAAAGAGTAACTTCCGGAGGCACAGAAGAAAGGGCGCAGCGAG GGCAATAGGGTGGAGAAGAGTTTTAGCTGGCTAGGACAGTGCCGCCTGAAATTATCAGCCTGCCAAGATT TAAACATAGATGAATGTGGCATAATCCCCCATCTCCAAAGTCCAAGGTCCATACGACCGTCCATAGCCCC TCTCGAGGCAGTGGTAGAGTCCCAGCTGGTGACTGTTTTTCAGGCATTTACGGTAGCCACCTCAATCTTC TAGCGCTCAAGCGCGCGCACAGACGTGAACGCCGCCAGAGGGGGGAGGGGGTGGGGCGATGCTTAAGTGT CCACGCATCCGTAGTGCGACGCACGCAGGCGTAGTACGGTCCCCCGGGCGACAGCGGTGGCGGCTCCTCG GGGTGCTCGGCTCCCTCCCACCTAGGCCGGCCCCGGCCCGACTCGCCCTCA
EPDnew 實驗支持 promoter/TSS · 4 筆
| EPDnew ID | TSS(1-based) | 股向 | 來源顯示區間 |
|---|---|---|---|
| BAG6_4 ↗ | 6:31,651,990 | 負股 | 31,651,980–31,652,039 |
| BAG6_3 ↗ | 6:31,652,389 | 負股 | 31,652,379–31,652,438 |
| BAG6_1 ↗ | 6:31,652,661 | 負股 | 31,652,651–31,652,710 |
| BAG6_2 ↗ | 6:31,660,769 | 負股 | 31,660,759–31,660,818 |
EPDnew human v006 · UCSC hg38,GRCh38/hg38,透過 UCSC 取得。TSS 具有 CAGE/RAMPAGE 等實驗資料支持;任意擷取的上下游區間仍需另行判讀調控功能,不能視為整段皆經功能驗證。
EPD 封存狀態 ↗ · UCSC 資料說明 ↗ · EPD team, SIB Swiss Institute of Bioinformatics; UCSC Genome Browser · CC BY 4.0
查看已取得的調控/motif 註解
ENSR6_65PHNG · promoter · 31652383–31652427 · regulatory
ENSR6_8X5FF · enhancer · 31652428–31652650 · regulatory
ENSR6_B89LF · promoter · 31652651–31653195 · regulatory
· motif · 31648529–31648540 · motif
· motif · 31651641–31651656 · motif
· motif · 31651702–31651724 · motif
· motif · 31651702–31651724 · motif
· motif · 31651892–31651904 · motif
· motif · 31651895–31651908 · motif
· motif · 31652073–31652086 · motif
· motif · 31652154–31652171 · motif
· motif · 31652172–31652183 · motif
· motif · 31652172–31652183 · motif
· motif · 31652376–31652389 · motif
· motif · 31652403–31652412 · motif
· motif · 31652403–31652414 · motif
· motif · 31652403–31652414 · motif
· motif · 31652403–31652417 · motif
· motif · 31652412–31652423 · motif
· motif · 31652438–31652447 · motif
· motif · 31652438–31652449 · motif
· motif · 31652438–31652449 · motif
· motif · 31652438–31652452 · motif
· motif · 31652479–31652488 · motif
· motif · 31652479–31652490 · motif
· motif · 31652479–31652490 · motif
· motif · 31652479–31652493 · motif
· motif · 31652621–31652634 · motif
· motif · 31652649–31652660 · motif
· motif · 31652649–31652660 · motif
· motif · 31652669–31652680 · motif
· motif · 31652669–31652680 · motif
· motif · 31652695–31652705 · motif
· motif · 31652697–31652707 · motif
· motif · 31652701–31652711 · motif
· motif · 31652839–31652854 · motif
· motif · 31652839–31652854 · motif
· motif · 31652840–31652854 · motif
· motif · 31652985–31652996 · motif
· motif · 31652987–31652996 · motif
· motif · 31653074–31653087 · motif
· motif · 31653079–31653089 · motif
· motif · 31653128–31653141 · motif
· motif · 31653738–31653747 · motif
· motif · 31653926–31653938 · motif
· motif · 31655675–31655689 · motif
· motif · 31655675–31655690 · motif
· motif · 31655852–31655867 · motif
· motif · 31655853–31655867 · motif
· motif · 31655858–31655870 · motif
· motif · 31655860–31655867 · motif
· motif · 31655860–31655873 · motif
· motif · 31655860–31655874 · motif
· motif · 31655860–31655875 · motif
蛋白質結構域與序列
參考蛋白質長度:1132 aa
BAG cochaperone 6 長 1,132 個胺基酸,N 端含 ubiquitin-like domain。蛋白質中段有四段約 29 個胺基酸的重複序列,並有多個註記為無序的區域。C 端含與 GET4 互作所需區域,以及足以促進客戶蛋白送往內質網的區域;BAG-similar domain 與 UBL4A 互作所需且足夠。另註記有核定位訊號。
蛋白質三維結構
細胞內定位
BAG6 通常位於細胞質與細胞核;與 GET4 互作有助於其滯留於細胞質。 腫瘤細胞及髓系樹突細胞也可將 BAG6 經胞外囊泡釋出。 DNA 損傷後,BAG6 會累積於細胞核。
深綠色圓點:來源記載的蛋白質定位;數量不表示含量。
細胞外定位:圓點散佈於細胞周圍,與細胞膜保持距離。
動物細胞結構示意;器官大小與數量不按比例。點選細胞構造可查看定位註解。
交互作用與訊號網絡
拖曳節點後放開可帶動位置變化;點選夥伴查看證據。位置與連線長度不代表結合強度,圖中未推定夥伴彼此之間的關係。
更多交互作用夥伴 · 已取得 143 個夥伴
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- ASIC4Q96FT7-4 · UniProt INTERACTION · 3 experiments
- ATP6V1B1P15313 · UniProt INTERACTION · 3 experiments
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BAG6 是 BAG6/BAT3 complex(亦稱 BAT3 complex)的成員,該複合體至少包含 BAG6、UBL4A 與 GET4/TRC35。BAG6 直接結合 GET4;也直接結合 UBL4A,且此互作對 UBL4A 的蛋白質穩定性有必要。BAG6 的 ubiquitin-like domain 可與 RNF126 或 SGTA 互作,兩者競爭同一區域;SGTA 的結合與目標蛋白去泛素化及避免降解有關。另有資料記載 BAG6 與 p300/EP300、AIFM1、HSPA2 等互作。微生物感染時,BAG6 也與 Legionella pneumophila 的 Lpg2160 及 LegU1 蛋白互作。
疾病與遺傳關聯
Contextual Functional Evidence Matrix
矩陣以「功能主張」為列,以細胞情境、干預條件、量測結果與證據來源為欄,方便比較同一功能在不同條件下的支持情形。只有含情境與實驗資訊的紀錄會列入矩陣;一般功能註解另列於下方。
功能註解總覽 · 7 筆
| 功能面向 | 功能敘述 | 證據類型 | 可查核來源 |
|---|---|---|---|
| 功能 | BAG6/BAT3 complex 維持錯誤摺疊或含疏水區段蛋白質的可溶性,並協助其送往內質網或蛋白酶體。它參與 tail-anchored 蛋白質送往內質網、錯置蛋白分流、ERAD 與新生多肽降解;部分免疫、生殖、凋亡及 IGF1R 訊號作用帶有可能性或相似性證據。 | 含實驗來源 | 證據與來源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 (By similarity). 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 (By similarity). Also positively regulates apoptosis by interacting with and stabilizing the pro-apoptotic factor AIFM1 (By similarity). By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway PMID 20516149 ↗ · PMID 20676083 ↗ · PMID 21636303 ↗ · PMID 21743475 ↗ · PMID 23129660 ↗ · PMID 24981174 ↗ · PMID 25179605 ↗ · PMID 26565908 ↗ · PMID 26692333 ↗ · PMID 27193484 ↗ · PMID 28104892 ↗ |
| 功能 | DNA 受損後,BAG6 會累積於細胞核並與 p300/EP300 形成複合體,增強 p300/EP300 介導的 p53/TP53 乙醯化及其轉錄活性。位於細胞核時,BAG6 也可能參與調控組蛋白 H3 Lys-4 二甲基化的染色質調節複合體。 | 含實驗來源 | 證據與來源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) PMID 17403783 ↗ · PMID 18765639 ↗ |
| 功能 | BAG6 可經胞外囊泡釋出,並作為自然殺手細胞受體 NCR3 的配體,刺激自然殺手細胞的細胞毒性。它可能因此引發自然殺手細胞對鄰近腫瘤細胞及未成熟髓系樹突細胞的細胞毒作用。 | 含實驗來源 | 證據與來源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) PMID 18055229 ↗ · PMID 18852879 ↗ |
| 功能 | BAG6 參與 ricin 所誘發的細胞凋亡。 | 含實驗來源 | |
| 交互作用 | BAG6 是至少由 BAG6、UBL4A 與 GET4/TRC35 組成的 BAG6/BAT3 complex 成員,並與多種蛋白質互作。其 ubiquitin-like domain 可結合 RNF126 或競爭性結合的 SGTA;後者與目標蛋白去泛素化及避免降解有關。BAG6 也直接結合 GET4、UBL4A,並與多個品質管制、凋亡及細胞核調控相關蛋白互作。 | 含實驗來源 | 證據與來源Component of the BAG6/BAT3 complex, also named BAT3 complex, at least composed of BAG6, UBL4A and GET4/TRC35. Interacts with GET4; the interaction is direct and localizes BAG6 in the cytosol. Interacts with UBL4A; the interaction is direct and required for UBL4A protein stability. Interacts with AIFM1 (By similarity). Interacts with HSPA2 (By similarity). Interacts with CTCFL. Interacts with p300/EP300. Interacts (via ubiquitin-like domain) with RNF126; required for BAG6-dependent ubiquitination of proteins mislocalized to the cytosol. Interacts (via ubiquitin-like domain) with SGTA; SGTA competes with RNF126 by binding the same region of BAG6, thereby promoting deubiquitination of BAG6-target proteins and rescuing them from degradation. Interacts with ricin A chain. Interacts with VCP and AMFR; both form the VCP/p97-AMFR/gp78 complex. Interacts with SYVN1. Interacts with USP13; the interaction is direct and may mediate UBL4A deubiquitination. Interacts with ZFAND2B. Interacts with KPNA2. Interacts with UBQLN4. Interacts with MUL1/MAPL PMID 14960581 ↗ · PMID 17403783 ↗ · PMID 18765639 ↗ · PMID 20676083 ↗ · PMID 21636303 ↗ · PMID 23129660 ↗ · PMID 24160817 ↗ · PMID 24424410 ↗ · PMID 24981174 ↗ · PMID 25179605 ↗ · PMID 25713138 ↗ · PMID 26337389 ↗ · PMID 27113755 ↗ · PMID 27193484 ↗ · PMID 29042515 ↗ · PMID 34887561 ↗ · PMID 40105103 ↗ |
| 交互作用 | 在微生物感染情境下,BAG6 與 Legionella pneumophila 的 Lpg2160 及 LegU1 蛋白互作。 | 含實驗來源 | |
| 細胞定位 | BAG6 通常位於細胞質與細胞核,並可由腫瘤細胞及髓系樹突細胞經胞外囊泡釋出。與 GET4 的互作促使 BAG6 滯留於細胞質。 | 含實驗來源 | 證據與來源Cytoplasm, cytosol; Nucleus; Secreted, extracellular exosome; Normally localized in cytosol and nucleus, it can also be released extracellularly, in exosomes, by tumor and myeloid dendritic cells. Cytoplasmic retention is due to interaction with GET4 PMID 17403783 ↗ · PMID 20676083 ↗ · PMID 21636303 ↗ · PMID 29042515 ↗ · PMID 14960581 ↗ · PMID 18055229 ↗ · PMID 18852879 ↗ |
核酸與蛋白質序列
GCACGCAGGCGTAGTACGGTCCCCCGGGCGACAGCGGTGG40CGGCTCCTCGGGGTGCTCGGCTCCCTCCCACCTAGGCCGG80CCCCGGCCCGACTCGCCCTCAGAAACTCACTGTTTGGGGC120TGCGGACTTTCTCGTCGTGCCCCACAAAAGTAAAGCTTGG160GGACCTGGGGGGAGCCGGAAGTATCGCTTCGAGATCCCCA200AATACTATCGGGGAAACGGAAGTGGCCGTCGGTGGCAGAG240ACCTGTCGGCCATGGAGCCTAATGATAGTACCAGTACCGC280TGTGGAGGAGCCTGACAGCTTGGAGGTGTTGGTGAAGACC320TTGGACTCTCAAACTCGTACCTTTATTGTGGGGGCCCAGA360TGAATGTAAAAGAGTTTAAGGAGCACATTGCTGCCTCTGT400CAGCATCCCATCTGAAAAACAACGGCTCATTTACCAGGGA440CGAGTTCTGCAAGATGATAAGAAGCTTCAGGAATACAATG480TTGGGGGAAAGGTTATCCACCTGGTGGAACGGGCTCCTCC520TCAGACTCACCTCCCTTCTGGGGCATCTTCTGGGACGGGG560TCTGCCTCAGCCACTCATGGTGGGGGATCCCCCCCTGGTA600CTCGGGGGCCTGGGGCCTCTGTTCATGACCGGAATGCCAA640CAGCTATGTCATGGTTGGAACCTTCAATCTTCCTAGTGAC680GGCTCTGCTGTGGATGTTCACATCAACATGGAACAGGCCC720CGATTCAGAGTGAGCCCCGGGTACGGCTGGTGATGGCTCA760GCACATGATCAGGGATATACAGACCTTACTATCCCGGATG800GAGTGTCGAGGAGGGCCCCAACCGCAGCACAGTCAGCCGC840CCCCGCAGCCACCGGCTGTGACCCCGGAGCCAGTAGCCTT880GAGCTCTCAAACATCAGAACCAGTTGAAAGTGAAGCACCT920CCCCGGGAGCCCATGGAGGCAGAAGAAGTGGAGGAGCGTG960cDNA 使用 DNA 字母 T;mRNA 模式改以 U 顯示。轉錄本保留已註解的非編碼區,未另外加入 poly(A) 尾;非編碼 RNA 的參考轉錄本也可能仍需後續加工。數字為所選序列的 1-based 位置。長序列以黃色捲軸瀏覽,可複製或下載完整轉錄本與蛋白質;基因組 DNA 隨捲動取得所需範圍。