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基本情報
登録情報 | データベース: PDB / ID: 7a08 | |||||||||||||||||||||||||||||||||||||||||||||
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タイトル | CryoEM Structure of cGAS Nucleosome complex | |||||||||||||||||||||||||||||||||||||||||||||
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![]() | TRANSFERASE / complex / immune protein / nuclear protein | |||||||||||||||||||||||||||||||||||||||||||||
機能・相同性 | ![]() negative regulation of chromosome condensation / Barr body / : / regulation of type I interferon production / 2',3'-cyclic GMP-AMP synthase activity / cyclic GMP-AMP synthase / inner kinetochore / pericentric heterochromatin formation / paracrine signaling / poly-ADP-D-ribose modification-dependent protein binding ...negative regulation of chromosome condensation / Barr body / : / regulation of type I interferon production / 2',3'-cyclic GMP-AMP synthase activity / cyclic GMP-AMP synthase / inner kinetochore / pericentric heterochromatin formation / paracrine signaling / poly-ADP-D-ribose modification-dependent protein binding / muscle cell differentiation / regulation of immunoglobulin production / negative regulation of DNA repair / cGAS/STING signaling pathway / oocyte maturation / regulation of T cell activation / cGMP-mediated signaling / nucleosomal DNA binding / negative regulation of cGAS/STING signaling pathway / cellular response to exogenous dsRNA / nucleus organization / spermatid development / positive regulation of type I interferon production / regulation of immune response / single fertilization / negative regulation of double-strand break repair via homologous recombination / subtelomeric heterochromatin formation / cAMP-mediated signaling / negative regulation of megakaryocyte differentiation / RNA polymerase II core promoter sequence-specific DNA binding / protein localization to CENP-A containing chromatin / nucleosome binding / Replacement of protamines by nucleosomes in the male pronucleus / CENP-A containing nucleosome / Packaging Of Telomere Ends / positive regulation of defense response to virus by host / Recognition and association of DNA glycosylase with site containing an affected purine / Cleavage of the damaged purine / phosphatidylinositol-4,5-bisphosphate binding / Deposition of new CENPA-containing nucleosomes at the centromere / Recognition and association of DNA glycosylase with site containing an affected pyrimidine / Cleavage of the damaged pyrimidine / embryo implantation / telomere organization / Inhibition of DNA recombination at telomere / RNA Polymerase I Promoter Opening / Meiotic synapsis / activation of innate immune response / Assembly of the ORC complex at the origin of replication / Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex / SUMOylation of chromatin organization proteins / DNA methylation / Condensation of Prophase Chromosomes / Chromatin modifications during the maternal to zygotic transition (MZT) / SIRT1 negatively regulates rRNA expression / HCMV Late Events / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / innate immune response in mucosa / PRC2 methylates histones and DNA / Regulation of endogenous retroelements by KRAB-ZFP proteins / Defective pyroptosis / determination of adult lifespan / HDMs demethylate histones / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / HDACs deacetylate histones / RNA Polymerase I Promoter Escape / Nonhomologous End-Joining (NHEJ) / Transcriptional regulation by small RNAs / molecular condensate scaffold activity / Formation of the beta-catenin:TCF transactivating complex / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / G2/M DNA damage checkpoint / Metalloprotease DUBs / NoRC negatively regulates rRNA expression / DNA Damage/Telomere Stress Induced Senescence / B-WICH complex positively regulates rRNA expression / PKMTs methylate histone lysines / Meiotic recombination / Pre-NOTCH Transcription and Translation / RMTs methylate histone arginines / Activation of anterior HOX genes in hindbrain development during early embryogenesis / multicellular organism growth / male gonad development / Transcriptional regulation of granulopoiesis / UCH proteinases / HCMV Early Events / antimicrobial humoral immune response mediated by antimicrobial peptide / osteoblast differentiation / structural constituent of chromatin / antibacterial humoral response / positive regulation of cellular senescence / E3 ubiquitin ligases ubiquitinate target proteins / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / nucleosome / site of double-strand break / heterochromatin formation / RUNX1 regulates transcription of genes involved in differentiation of HSCs / nucleosome assembly / Processing of DNA double-strand break ends 類似検索 - 分子機能 | |||||||||||||||||||||||||||||||||||||||||||||
生物種 | ![]() ![]() ![]() synthetic construct (人工物) | |||||||||||||||||||||||||||||||||||||||||||||
手法 | 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.11 Å | |||||||||||||||||||||||||||||||||||||||||||||
![]() | Michalski, S. / de Oliveira Mann, C.C. / Witte, G. / Bartho, J. / Lammens, K. / Hopfner, K.P. | |||||||||||||||||||||||||||||||||||||||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Structural basis for sequestration and autoinhibition of cGAS by chromatin. 著者: Sebastian Michalski / Carina C de Oliveira Mann / Che A Stafford / Gregor Witte / Joseph Bartho / Katja Lammens / Veit Hornung / Karl-Peter Hopfner / ![]() 要旨: Cyclic GMP-AMP synthase (cGAS) is an innate immune sensor for cytosolic microbial DNA. After binding DNA, cGAS synthesizes the messenger 2'3'-cyclic GMP-AMP (cGAMP), which triggers cell-autonomous ...Cyclic GMP-AMP synthase (cGAS) is an innate immune sensor for cytosolic microbial DNA. After binding DNA, cGAS synthesizes the messenger 2'3'-cyclic GMP-AMP (cGAMP), which triggers cell-autonomous defence and the production of type I interferons and pro-inflammatory cytokines via the activation of STING. In addition to responding to cytosolic microbial DNA, cGAS also recognizes mislocalized cytosolic self-DNA and has been implicated in autoimmunity and sterile inflammation. Specificity towards pathogen- or damage-associated DNA was thought to be caused by cytosolic confinement. However, recent findings place cGAS robustly in the nucleus, where tight tethering of chromatin is important to prevent autoreactivity to self-DNA. Here we show how cGAS is sequestered and inhibited by chromatin. We provide a cryo-electron microscopy structure of the cGAS catalytic domain bound to a nucleosome, which shows that cGAS does not interact with the nucleosomal DNA, but instead interacts with histone 2A-histone 2B, and is tightly anchored to the 'acidic patch'. The interaction buries the cGAS DNA-binding site B, and blocks the formation of active cGAS dimers. The acidic patch robustly outcompetes agonistic DNA for binding to cGAS, which suggests that nucleosome sequestration can efficiently inhibit cGAS, even when accessible DNA is nearby, such as in actively transcribed genomic regions. Our results show how nuclear cGAS is sequestered by chromatin and provides a mechanism for preventing autoreactivity to nuclear self-DNA. | |||||||||||||||||||||||||||||||||||||||||||||
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構造の表示
ムービー |
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構造ビューア | 分子: ![]() ![]() |
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ダウンロードとリンク
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ダウンロード
PDBx/mmCIF形式 | ![]() | 331.7 KB | 表示 | ![]() |
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PDB形式 | ![]() | 248.9 KB | 表示 | ![]() |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
文書・要旨 | ![]() | 843.4 KB | 表示 | ![]() |
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文書・詳細版 | ![]() | 863.8 KB | 表示 | |
XML形式データ | ![]() | 42 KB | 表示 | |
CIF形式データ | ![]() | 66.3 KB | 表示 | |
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
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リンク
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集合体
登録構造単位 | ![]()
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要素
-タンパク質 , 5種, 9分子 abfcgdhei
#1: タンパク質 | 分子量: 43401.180 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() ![]() | ||||||
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#4: タンパク質 | 分子量: 14004.329 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() #5: タンパク質 | 分子量: 13806.018 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 遺伝子: HIST1H2BC, H2BFL, HIST1H2BE, H2BFH, HIST1H2BF, H2BFG, HIST1H2BG, H2BFA, HIST1H2BI, H2BFK 発現宿主: ![]() ![]() #6: タンパク質 | 分子量: 15229.787 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 遺伝子: H3-3A, H3.3A, H3F3, H3F3A, PP781, H3-3B, H3.3B, H3F3B 発現宿主: ![]() ![]() #7: タンパク質 | 分子量: 11263.231 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 遺伝子: HIST1H4A, H4/A, H4FA, HIST1H4B, H4/I, H4FI, HIST1H4C, H4/G, H4FG, HIST1H4D, H4/B, H4FB, HIST1H4E, H4/J, H4FJ, HIST1H4F, H4/C, H4FC, HIST1H4H, H4/H, H4FH, HIST1H4I, H4/M, H4FM, HIST1H4J, ...遺伝子: HIST1H4A, H4/A, H4FA, HIST1H4B, H4/I, H4FI, HIST1H4C, H4/G, H4FG, HIST1H4D, H4/B, H4FB, HIST1H4E, H4/J, H4FJ, HIST1H4F, H4/C, H4FC, HIST1H4H, H4/H, H4FH, HIST1H4I, H4/M, H4FM, HIST1H4J, H4/E, H4FE, HIST1H4K, H4/D, H4FD, HIST1H4L, H4/K, H4FK, HIST2H4A, H4/N, H4F2, H4FN, HIST2H4, HIST2H4B, H4/O, H4FO, HIST4H4 発現宿主: ![]() ![]() |
-Nucleosomal DNA strand ... , 2種, 2分子 IJ
#2: DNA鎖 | 分子量: 45145.754 Da / 分子数: 1 / 由来タイプ: 合成 / 由来: (合成) synthetic construct (人工物) |
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#3: DNA鎖 | 分子量: 45604.047 Da / 分子数: 1 / 由来タイプ: 合成 / 由来: (合成) synthetic construct (人工物) |
-非ポリマー , 1種, 1分子 
#8: 化合物 | ChemComp-ZN / |
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-詳細
研究の焦点であるリガンドがあるか | N |
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Has protein modification | Y |
-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
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EM実験 | 試料の集合状態: PARTICLE / 3次元再構成法: 単粒子再構成法 |
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試料調製
構成要素 |
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分子量 |
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由来(天然) |
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由来(組換発現) |
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緩衝液 | pH: 7.5 | ||||||||||||||||||||||||||||||
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES | ||||||||||||||||||||||||||||||
試料支持 | グリッドの材料: COPPER / グリッドのタイプ: Quantifoil | ||||||||||||||||||||||||||||||
急速凍結 | 凍結剤: ETHANE |
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電子顕微鏡撮影
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
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顕微鏡 | モデル: FEI TITAN KRIOS |
電子銃 | 電子線源: ![]() |
電子レンズ | モード: BRIGHT FIELD |
撮影 | 電子線照射量: 44.8 e/Å2 フィルム・検出器のモデル: GATAN K2 SUMMIT (4k x 4k) |
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解析
ソフトウェア | 名称: PHENIX / バージョン: 1.18.2_3874: / 分類: 精密化 | ||||||||||||||||||||||||
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EMソフトウェア | 名称: PHENIX / カテゴリ: モデル精密化 | ||||||||||||||||||||||||
CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3次元再構成 | 解像度: 3.11 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 172977 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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