Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Science
2020 Oct 23;3706515:455-458. doi: 10.1126/science.abd0237.
Show Gene links
Show Anatomy links
Structural basis for the inhibition of cGAS by nucleosomes.
Kujirai T, Zierhut C, Takizawa Y, Kim R, Negishi L, Uruma N, Hirai S, Funabiki H, Kurumizaka H.
???displayArticle.abstract???
The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) senses invasion of pathogenic DNA and stimulates inflammatory signaling, autophagy, and apoptosis. Organization of host DNA into nucleosomes was proposed to limit cGAS autoinduction, but the underlying mechanism was unknown. Here, we report the structural basis for this inhibition. In the cryo-electron microscopy structure of the human cGAS-nucleosome core particle (NCP) complex, two cGAS monomers bridge two NCPs by binding the acidic patch of the histone H2A-H2B dimer and nucleosomal DNA. In this configuration, all three known cGAS DNA binding sites, required for cGAS activation, are repurposed or become inaccessible, and cGAS dimerization, another prerequisite for activation, is inhibited. Mutating key residues linking cGAS and the acidic patch alleviates nucleosomal inhibition. This study establishes a structural framework for why cGAS is silenced on chromatinized self-DNA.
Ablasser,
cGAS in action: Expanding roles in immunity and inflammation.
2019, Pubmed
Ablasser,
cGAS in action: Expanding roles in immunity and inflammation.
2019,
Pubmed Ablasser,
cGAS produces a 2'-5'-linked cyclic dinucleotide second messenger that activates STING.
2013,
Pubmed Andreeva,
cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein-DNA ladders.
2017,
Pubmed Arimura,
Structural analysis of the hexasome, lacking one histone H2A/H2B dimer from the conventional nucleosome.
2012,
Pubmed Barad,
EMRinger: side chain-directed model and map validation for 3D cryo-electron microscopy.
2015,
Pubmed Civril,
Structural mechanism of cytosolic DNA sensing by cGAS.
2013,
Pubmed de la Rosa-Trevín,
Scipion: A software framework toward integration, reproducibility and validation in 3D electron microscopy.
2016,
Pubmed Du,
DNA-induced liquid phase condensation of cGAS activates innate immune signaling.
2018,
Pubmed Emsley,
Features and development of Coot.
2010,
Pubmed Gao,
Cyclic [G(2',5')pA(3',5')p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase.
2013,
Pubmed Gentili,
The N-Terminal Domain of cGAS Determines Preferential Association with Centromeric DNA and Innate Immune Activation in the Nucleus.
2019,
Pubmed Hooy,
The allosteric activation of cGAS underpins its dynamic signaling landscape.
2018,
Pubmed Ishikawa,
STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity.
2009,
Pubmed Ishikawa,
STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling.
2008,
Pubmed Jiang,
Chromatin-bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death.
2019,
Pubmed Kalashnikova,
The role of the nucleosome acidic patch in modulating higher order chromatin structure.
2013,
Pubmed Kastner,
GraFix: sample preparation for single-particle electron cryomicroscopy.
2008,
Pubmed Kato,
Cyclic GMP-AMP as an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA.
2017,
Pubmed Kim,
Cryo_fit: Democratization of flexible fitting for cryo-EM.
2019,
Pubmed Kujirai,
Methods for Preparing Nucleosomes Containing Histone Variants.
2018,
Pubmed Lahaye,
NONO Detects the Nuclear HIV Capsid to Promote cGAS-Mediated Innate Immune Activation.
2018,
Pubmed Li,
Cyclic GMP-AMP synthase is activated by double-stranded DNA-induced oligomerization.
2013,
Pubmed Liebschner,
Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix.
2019,
Pubmed Lowary,
New DNA sequence rules for high affinity binding to histone octamer and sequence-directed nucleosome positioning.
1998,
Pubmed Mackenzie,
cGAS surveillance of micronuclei links genome instability to innate immunity.
2017,
Pubmed Mastronarde,
Automated electron microscope tomography using robust prediction of specimen movements.
2005,
Pubmed Motwani,
DNA sensing by the cGAS-STING pathway in health and disease.
2019,
Pubmed Murray,
Cell cycle extracts.
1991,
Pubmed Pettersen,
UCSF Chimera--a visualization system for exploratory research and analysis.
2004,
Pubmed Ramírez-Aportela,
Automatic local resolution-based sharpening of cryo-EM maps.
2020,
Pubmed Sun,
Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway.
2013,
Pubmed Tan,
Addressing preferred specimen orientation in single-particle cryo-EM through tilting.
2017,
Pubmed Vasudevan,
Crystal structures of nucleosome core particles containing the '601' strong positioning sequence.
2010,
Pubmed
,
Xenbase Vilas,
MonoRes: Automatic and Accurate Estimation of Local Resolution for Electron Microscopy Maps.
2018,
Pubmed Volkman,
Tight nuclear tethering of cGAS is essential for preventing autoreactivity.
2019,
Pubmed Williams,
MolProbity: More and better reference data for improved all-atom structure validation.
2018,
Pubmed Wu,
Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA.
2013,
Pubmed Xie,
Human cGAS catalytic domain has an additional DNA-binding interface that enhances enzymatic activity and liquid-phase condensation.
2019,
Pubmed Yang,
cGAS is essential for cellular senescence.
2017,
Pubmed Zhang,
The cytosolic DNA sensor cGAS forms an oligomeric complex with DNA and undergoes switch-like conformational changes in the activation loop.
2014,
Pubmed Zhang,
Gctf: Real-time CTF determination and correction.
2016,
Pubmed Zheng,
MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy.
2017,
Pubmed Zhong,
Phosphorylation of cGAS by CDK1 impairs self-DNA sensing in mitosis.
2020,
Pubmed Zhou,
Structure of the Human cGAS-DNA Complex Reveals Enhanced Control of Immune Surveillance.
2018,
Pubmed Zierhut,
Nucleosomal regulation of chromatin composition and nuclear assembly revealed by histone depletion.
2014,
Pubmed
,
Xenbase Zierhut,
The Cytoplasmic DNA Sensor cGAS Promotes Mitotic Cell Death.
2019,
Pubmed Zivanov,
New tools for automated high-resolution cryo-EM structure determination in RELION-3.
2018,
Pubmed
