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Structure of the Human cGAS–DNA Complex Reveals Enhanced Control of Immune Surveillance

Zhou, Wen ; Whiteley, Aaron T. ; de Oliveira Mann, Carina C. ; Morehouse, Benjamin R. ; Nowak, Radosław P. ; Fischer, Eric S. ; Gray, Nathanael S. ; Mekalanos, John J. ; Kranzusch, Philip J.

Cell, 2018-07, Vol.174 (2), p.300-311.e11 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Structure of the Human cGAS–DNA Complex Reveals Enhanced Control of Immune Surveillance
Autor: Zhou, Wen ; Whiteley, Aaron T. ; de Oliveira Mann, Carina C. ; Morehouse, Benjamin R. ; Nowak, Radosław P. ; Fischer, Eric S. ; Gray, Nathanael S. ; Mekalanos, John J. ; Kranzusch, Philip J.
Assuntos: Animals ; Benzofurans - chemistry ; Benzofurans - metabolism ; Binding Sites ; Catalytic Domain ; cGAS ; Chemotaxis - drug effects ; DNA - chemistry ; DNA - metabolism ; Humans ; Immunologic Surveillance - physiology ; innate immunity ; Mice ; Molecular Docking Simulation ; Mutagenesis, Site-Directed ; Nucleotides, Cyclic - metabolism ; Nucleotides, Cyclic - pharmacology ; Nucleotidyltransferases - antagonists & inhibitors ; Nucleotidyltransferases - genetics ; Nucleotidyltransferases - metabolism ; Protein Multimerization ; Protein Structure, Tertiary ; Recombinant Proteins - biosynthesis ; Recombinant Proteins - chemistry ; Recombinant Proteins - isolation & purification ; Species Specificity ; STING ; structural biology ; Vibrio cholerae - metabolism ; Vibrio cholerae - physiology
É parte de: Cell, 2018-07, Vol.174 (2), p.300-311.e11
Notas: National Institutes of Health (NIH)
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These authors contributed equally
Descrição: Cyclic GMP–AMP synthase (cGAS) recognition of cytosolic DNA is critical for immune responses to pathogen replication, cellular stress, and cancer. Existing structures of the mouse cGAS–DNA complex provide a model for enzyme activation but do not explain why human cGAS exhibits severely reduced levels of cyclic GMP–AMP (cGAMP) synthesis compared to other mammals. Here, we discover that enhanced DNA-length specificity restrains human cGAS activation. Using reconstitution of cGAMP signaling in bacteria, we mapped the determinant of human cGAS regulation to two amino acid substitutions in the DNA-binding surface. Human-specific substitutions are necessary and sufficient to direct preferential detection of long DNA. Crystal structures reveal why removal of human substitutions relaxes DNA-length specificity and explain how human-specific DNA interactions favor cGAS oligomerization. These results define how DNA-sensing in humans adapted for enhanced specificity and provide a model of the active human cGAS–DNA complex to enable structure-guided design of cGAS therapeutics. [Display omitted] •cGAS-DNA-sensing in humans is adapted for enhanced specificity•A bacterial genetic assay allows rapid mapping of human cGAS regulatory determinant•Human cGAS–DNA structures reveal altered contacts that favor DNA-length discrimination•cGAS active site variation explains species-specificity of small-molecule inhibitors The structure of the human cGAS–DNA complex reveals regulatory adaptations that balance enzymatic activity with DNA-length sensitivity, and additional features important for drug design.
Editor: United States: Elsevier Inc
Idioma: Inglês

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Structure of the Human cGAS–DNA Complex Reveals Enhanced Control of Immune Surveillance

Zhou, Wen ; Whiteley, Aaron T. ; de Oliveira Mann, Carina C. ; Morehouse, Benjamin R. ; Nowak, Radosław P. ; Fischer, Eric S. ; Gray, Nathanael S. ; Mekalanos, John J. ; Kranzusch, Philip J.

United States: Elsevier Inc

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