The allosteric activation of cGAS underpins its dynamic signaling landscape
Cyclic G/AMP synthase (cGAS) initiates type-1 interferon responses against cytosolic double-stranded (ds)DNA, which range from antiviral gene expression to apoptosis. The mechanism by which cGAS shapes this diverse signaling landscape remains poorly defined. We find that substrate-binding and dsDNA...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2018-10-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/39984 |
| _version_ | 1811181127797309440 |
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| author | Richard M Hooy Jungsan Sohn |
| author_facet | Richard M Hooy Jungsan Sohn |
| author_sort | Richard M Hooy |
| collection | DOAJ |
| description | Cyclic G/AMP synthase (cGAS) initiates type-1 interferon responses against cytosolic double-stranded (ds)DNA, which range from antiviral gene expression to apoptosis. The mechanism by which cGAS shapes this diverse signaling landscape remains poorly defined. We find that substrate-binding and dsDNA length-dependent binding are coupled to the intrinsic dimerization equilibrium of cGAS, with its N-terminal domain potentiating dimerization. Notably, increasing the dimeric fraction by raising cGAS and substrate concentrations diminishes duplex length-dependent activation, but does not negate the requirement for dsDNA. These results demonstrate that reaction context dictates the duplex length dependence, reconciling competing claims on the role of dsDNA length in cGAS activation. Overall, our study reveals how ligand-mediated allostery positions cGAS in standby, ready to tune its signaling pathway in a switch-like fashion. |
| first_indexed | 2024-04-11T09:14:27Z |
| format | Article |
| id | doaj.art-f5d15df6b52c4f2d908057af9ec61efa |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:14:27Z |
| publishDate | 2018-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-f5d15df6b52c4f2d908057af9ec61efa2022-12-22T04:32:25ZengeLife Sciences Publications LtdeLife2050-084X2018-10-01710.7554/eLife.39984The allosteric activation of cGAS underpins its dynamic signaling landscapeRichard M Hooy0https://orcid.org/0000-0001-8917-0249Jungsan Sohn1https://orcid.org/0000-0002-9570-2544Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, United StatesDepartment of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, United StatesCyclic G/AMP synthase (cGAS) initiates type-1 interferon responses against cytosolic double-stranded (ds)DNA, which range from antiviral gene expression to apoptosis. The mechanism by which cGAS shapes this diverse signaling landscape remains poorly defined. We find that substrate-binding and dsDNA length-dependent binding are coupled to the intrinsic dimerization equilibrium of cGAS, with its N-terminal domain potentiating dimerization. Notably, increasing the dimeric fraction by raising cGAS and substrate concentrations diminishes duplex length-dependent activation, but does not negate the requirement for dsDNA. These results demonstrate that reaction context dictates the duplex length dependence, reconciling competing claims on the role of dsDNA length in cGAS activation. Overall, our study reveals how ligand-mediated allostery positions cGAS in standby, ready to tune its signaling pathway in a switch-like fashion.https://elifesciences.org/articles/39984innate immunityallosterycGAScytoplasmic DNAenzymologymechanisms |
| spellingShingle | Richard M Hooy Jungsan Sohn The allosteric activation of cGAS underpins its dynamic signaling landscape eLife innate immunity allostery cGAS cytoplasmic DNA enzymology mechanisms |
| title | The allosteric activation of cGAS underpins its dynamic signaling landscape |
| title_full | The allosteric activation of cGAS underpins its dynamic signaling landscape |
| title_fullStr | The allosteric activation of cGAS underpins its dynamic signaling landscape |
| title_full_unstemmed | The allosteric activation of cGAS underpins its dynamic signaling landscape |
| title_short | The allosteric activation of cGAS underpins its dynamic signaling landscape |
| title_sort | allosteric activation of cgas underpins its dynamic signaling landscape |
| topic | innate immunity allostery cGAS cytoplasmic DNA enzymology mechanisms |
| url | https://elifesciences.org/articles/39984 |
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