title: Structural mechanism of cytosolic DNA sensing by cGAS.
abstract: Cytosolic DNA arising from intracellular bacterial or viral infections is a powerful pathogen-associated molecular pattern (PAMP) that leads to innate immune host defence by the production of type I interferon and inflammatory cytokines. Recognition of cytosolic DNA by the recently discovered cyclic-GMP-AMP (cGAMP) synthase (cGAS) induces the production of cGAMP to activate the stimulator of interferon genes (STING). Here we report the crystal structure of cGAS alone and in complex with DNA, ATP and GTP along with functional studies. Our results explain the broad DNA sensing specificity of cGAS, show how cGAS catalyses dinucleotide formation and indicate activation by a DNA-induced structural switch. cGAS possesses a remarkable structural similarity to the antiviral cytosolic double-stranded RNA sensor 2'-5'oligoadenylate synthase (OAS1), but contains a unique zinc thumb that recognizes B-form double-stranded DNA. Our results mechanistically unify dsRNA and dsDNA innate immune sensing by OAS1 and cGAS nucleotidyl transferases.
authors.affiliation: Department of Biochemistry and Gene Center, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors.forename: Filiz
authors.initials: F
authors.lastname: Civril
authors.forename: Tobias
authors.initials: T
authors.lastname: Deimling
authors.forename: Carina C
authors.initials: CC
authors.lastname: de Oliveira Mann
authors.forename: Andrea
authors.initials: A
authors.lastname: Ablasser
authors.forename: Manuela
authors.initials: M
authors.lastname: Moldt
authors.forename: Gregor
authors.initials: G
authors.lastname: Witte
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.forename: Karl-Peter
authors.initials: KP
authors.lastname: Hopfner
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D003600:Cytosol; D004247:DNA / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D009154:Mutation; D009713:Nucleotidyltransferases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation / Q000187:drug effects; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013552:Swine; D014544:Uridine Triphosphate / Q000737:chemistry / Q000378:metabolism; D015032:Zinc / Q000737:chemistry / Q000378:metabolism; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D000255:Adenosine Triphosphate; D004247:DNA; D006160:Guanosine Triphosphate; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; D014544:Uridine Triphosphate; D015032:Zinc; C530855:Sting1 protein, mouse; D000099197:STING Protein; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase