- 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
: / Barr body / 2',3'-cyclic GMP-AMP synthase activity / cyclic GMP-AMP synthase / regulation of type I interferon production / negative regulation of chromosome condensation / paracrine signaling / pericentric heterochromatin formation / inner kinetochore / poly-ADP-D-ribose modification-dependent protein binding ...: / Barr body / 2',3'-cyclic GMP-AMP synthase activity / cyclic GMP-AMP synthase / regulation of type I interferon production / negative regulation of chromosome condensation / paracrine signaling / pericentric heterochromatin formation / inner kinetochore / poly-ADP-D-ribose modification-dependent protein binding / regulation of immunoglobulin production / muscle cell differentiation / : / oocyte maturation / regulation of T cell activation / cGAS/STING signaling pathway / nucleosomal DNA binding / pattern recognition receptor signaling pathway / negative regulation of DNA repair / negative regulation of cGAS/STING signaling pathway / nucleus organization / cellular response to exogenous dsRNA / cytoplasmic pattern recognition receptor signaling pathway / spermatid development / regulation of immune response / single fertilization / subtelomeric heterochromatin formation / negative regulation of double-strand break repair via homologous recombination / RNA polymerase II core promoter sequence-specific DNA binding / nucleosome binding / negative regulation of megakaryocyte differentiation / protein localization to CENP-A containing chromatin / positive regulation of defense response to virus by host / Replacement of protamines by nucleosomes in the male pronucleus / CENP-A containing nucleosome / positive regulation of type I interferon production / phosphatidylinositol-4,5-bisphosphate binding / Packaging Of Telomere Ends / Recognition and association of DNA glycosylase with site containing an affected purine / Cleavage of the damaged purine / embryo implantation / activation of innate immune response / Deposition of new CENPA-containing nucleosomes at the centromere / telomere organization / Recognition and association of DNA glycosylase with site containing an affected pyrimidine / Cleavage of the damaged pyrimidine / RNA Polymerase I Promoter Opening / Inhibition of DNA recombination at telomere / Assembly of the ORC complex at the origin of replication / Meiotic synapsis / SUMOylation of chromatin organization proteins / Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex / DNA methylation / Condensation of Prophase Chromosomes / Chromatin modifications during the maternal to zygotic transition (MZT) / SIRT1 negatively regulates rRNA expression / HCMV Late Events / determination of adult lifespan / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / PRC2 methylates histones and DNA / innate immune response in mucosa / Regulation of endogenous retroelements by KRAB-ZFP proteins / Defective pyroptosis / HDACs deacetylate histones / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / Nonhomologous End-Joining (NHEJ) / RNA Polymerase I Promoter Escape / molecular condensate scaffold activity / Transcriptional regulation by small RNAs / Formation of the beta-catenin:TCF transactivating complex / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / HDMs demethylate histones / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / G2/M DNA damage checkpoint / Negative Regulation of CDH1 Gene Transcription / NoRC negatively regulates rRNA expression / PKMTs methylate histone lysines / B-WICH complex positively regulates rRNA expression / DNA Damage/Telomere Stress Induced Senescence / Pre-NOTCH Transcription and Translation / male gonad development / Meiotic recombination / multicellular organism growth / Activation of anterior HOX genes in hindbrain development during early embryogenesis / Metalloprotease DUBs / Transcriptional regulation of granulopoiesis / RMTs methylate histone arginines / HCMV Early Events / osteoblast differentiation / structural constituent of chromatin / positive regulation of cellular senescence / UCH proteinases / nucleosome / antimicrobial humoral immune response mediated by antimicrobial peptide / heterochromatin formation / nucleosome assembly / E3 ubiquitin ligases ubiquitinate target proteins / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / antibacterial humoral response / 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.