Science: The cGAS suppression mechanism that structurally reveals the dependence of nuclear small bodies.

September 16, 2020 /--- In a new study, researchers at the University of North Carolina at Chapel Hill identified for the first time a high-resolution structure in the innate immune system in which a key DNA-sensing protein called cGAS binds to a nucleus, the most important UNIT of DNA packaging in the nucleus.
results were published online September 10, 2020 in the journal Science under the title "Structural basis of nucleosome-dependent cGAS resedion".
high-resolution structure when the protein cGAS (blue-green, top) is combined with the nucleosome, pictured from UNC-Chapel Hill.
study details how nucleosomes in our cells prevent cGAS from inadvertently triggering the body's innate immune response to its own DNA.
the paper is co-authored by Dr. Qi Zhang, Associate Professor of Biochemistry and Biophysics, Faculty of Medicine, University of North Carolina at Chapel Hill, and Dr. Robert McGinty, Assistant Professor of Chemical Biology and Pharmaceutical Chemistry, Esherman School of Pharmacy, University of North Carolina, Chapel Hill.
detection and response of foreign DNA from bacterial and viral pathogens is one of the most basic mechanisms of host defense," zhang said.
understanding of the function and regulation of this important DNA sensing protein will have a profound impact on basic research and human transformation of cGAS targeted therapies critical to improving human health.
"This study is based on the latest advances in cryogenic electroscopy, which allows scientists, like those on our team, to observe protein machines in our cells with unprecedented clarity," McGinty said.
see how these proteins function properly, we can gain insight into how to manipulate their function to treat disease.
in mammals' innogeneian immune systems, this protein, called ring-shaped GMP-AMP lysase (cGAS), detects foreign DNA or damaged "self" DNA.
when DNA is detected, cGAS synthesizes ring GMP-AMP (cGAMP), a second messenger molecule that activates the cGAS-STING signaling path, to fight infections, inflammatory diseases and cancer.
because cGAS is a "universal" DNA sensing protein, it must be regulated to distinguish pathogenic DNA from the body's own health DNA and avoid any unintended immune response.
previous studies have shown that cGAS is rich in the nucleus of the cells where our genome DNA is stored, but how cGAS ignores our own healthy DNA remains a mystery.
using the state-of-the-art frozen electroscope core facility at the University of North Carolina at Chapel Hill School of Medicine, established in 2019, Zhang and McGinty Labs identified a 3.3-E resolution frozen electromirror structure when cGAS is combined with a nuclear microsome.
this structure shows that cGAS uses two conservative amino acids to anchor on a negatively charged acidic pocket (acid patch) on the surface of the nucleosome.
these protein-protein interactions allow the nucleosome to occupy a key DNA sensing surface on cGAS and prevent cGAS from entering its functionally active DNA binding state.
combined with mutation and functional assays, this study describes how cGAS maintains a stationary, inhibitory state in the nucleus at near-atomic resolution.
McGinty said, "These findings reshape the current pattern of cGAS regulation and provide examples of the role of nucleosomes in regulating different protein functions."
"Biomedical scientists will be able to apply our research to immunology, cancer biology, and gene regulation, as well as drug discovery for infections, inflammatory diseases, and cancers," Zhang added.
" (bioon.com) Reference: 1. Joshua A. Boyer et al. Structural basiss of nucleosome-dependent cGAS resedion. Science, 2020, doi:10.1126/science.abd0609.2.Researchers reveal safeguarding of key DNA sensor innate immune system.