- EMDB-11601: CryoEM Structure of cGAS Nucleosome complex -
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基本情報
登録情報
データベース: EMDB / ID: EMD-11601
タイトル
CryoEM Structure of cGAS Nucleosome complex
マップデータ
試料
複合体: cGAS, Nucleosome and DNA
複合体: Nucleosome
タンパク質・ペプチド: Histone H2A type 1-C
タンパク質・ペプチド: Histone H2B type 1-C/E/F/G/I
タンパク質・ペプチド: Histone H3.3
タンパク質・ペプチド: Histone H4
複合体: Nucleosomal DNA strands 1 and 2
DNA: Nucleosomal DNA strand 1
DNA: Nucleosomal DNA strand 2
複合体: cGAS
タンパク質・ペプチド: Cyclic GMP-AMP synthase
リガンド: ZINC ION
キーワード
complex / immune protein / nuclear protein / TRANSFERASE
機能・相同性
機能・相同性情報
negative regulation of chromosome condensation / Barr body / regulation of centromere complex assembly / regulation of type I interferon production / 2',3'-cyclic GMP-AMP synthase activity / cyclic GMP-AMP synthase / pericentric heterochromatin formation / inner kinetochore / paracrine signaling / poly-ADP-D-ribose modification-dependent protein binding ...negative regulation of chromosome condensation / Barr body / regulation of centromere complex assembly / regulation of type I interferon production / 2',3'-cyclic GMP-AMP synthase activity / cyclic GMP-AMP synthase / pericentric heterochromatin formation / inner kinetochore / 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 / single fertilization / positive regulation of type I interferon production / regulation of immune response / negative regulation of double-strand break repair via homologous recombination / negative regulation of megakaryocyte differentiation / subtelomeric heterochromatin formation / protein localization to CENP-A containing chromatin / cAMP-mediated signaling / RNA polymerase II core promoter sequence-specific DNA binding / Replacement of protamines by nucleosomes in the male pronucleus / CENP-A containing nucleosome / nucleosome binding / Packaging Of Telomere Ends / Recognition and association of DNA glycosylase with site containing an affected purine / Cleavage of the damaged purine / positive regulation of defense response to virus by host / phosphatidylinositol-4,5-bisphosphate binding / Recognition and association of DNA glycosylase with site containing an affected pyrimidine / Cleavage of the damaged pyrimidine / Deposition of new CENPA-containing nucleosomes at the centromere / embryo implantation / telomere organization / Inhibition of DNA recombination at telomere / Meiotic synapsis / RNA Polymerase I Promoter Opening / 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 / innate immune response in mucosa / SUMOylation of chromatin organization proteins / DNA methylation / Condensation of Prophase Chromosomes / Chromatin modifications during the maternal to zygotic transition (MZT) / HCMV Late Events / SIRT1 negatively regulates rRNA expression / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / PRC2 methylates histones and DNA / Regulation of endogenous retroelements by KRAB-ZFP proteins / Defective pyroptosis / determination of adult lifespan / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / HDACs deacetylate histones / Nonhomologous End-Joining (NHEJ) / RNA Polymerase I Promoter Escape / Transcriptional regulation by small RNAs / Formation of the beta-catenin:TCF transactivating complex / molecular condensate scaffold activity / 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 / HDMs demethylate histones / NoRC negatively regulates rRNA expression / multicellular organism growth / DNA Damage/Telomere Stress Induced Senescence / B-WICH complex positively regulates rRNA expression / PKMTs methylate histone lysines / Meiotic recombination / Pre-NOTCH Transcription and Translation / Metalloprotease DUBs / RMTs methylate histone arginines / Activation of anterior HOX genes in hindbrain development during early embryogenesis / Transcriptional regulation of granulopoiesis / HCMV Early Events / antimicrobial humoral immune response mediated by antimicrobial peptide / positive regulation of cellular senescence / male gonad development / osteoblast differentiation / structural constituent of chromatin / antibacterial humoral response / UCH proteinases / nucleosome / heterochromatin formation / E3 ubiquitin ligases ubiquitinate target proteins / nucleosome assembly / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / chromatin organization / site of double-strand break / HATs acetylate histones 類似検索 - 分子機能
ジャーナル: Nature / 年: 2020 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.