Role of the Nucleosome in Regulating Protein Functions Revealed

Researchers have determined the high-resolution structure of cyclic GMP-AMP synthase (cGAS) while it is bound to the nucleosome. The team from the University of North Carolina at Chapel Hill published their results in Science. 

Their study reveals in detail how the nucleosomes inside our cells block cGAS from unintentionally triggering the body's innate immune response to our own DNA. "Detecting and responding to foreign DNA from bacterial and viral pathogens is one of the most fundamental mechanisms for host defense," said Qi Zhang, co-senior author. "A deeper understanding of functions and regulations of this important DNA sensor will have profound impacts on both basic research and translational development of cGAS-targeted therapeutics crucial to the betterment of human health."

Using cryo-electron microscopy, the team was able to determine that cGAS employs two conserved amino acids to anchor to a negatively charged patch on the nucleosome surface. The protein-protein interactions allow the nucleosome to occupy a critical DNA sensing surface on cGAS and prevent cGAS from entering its functionally active DNA-bound state. 

Through mutagenesis and functional analysis, the study provides a near-atomic resolution depiction of how cGAS maintains the resting, inhibited state in the nucleus. Robert McGinty, the co-senior author, said, "This work was enabled by recent advances in cryo-electron microscopy technology that allows scientists, like those on our team, to observe the protein machines inside our cells with unprecedented clarity. By seeing how these proteins function normally, we can gain insights into how to manipulate their functions to treat diseases."

Since cGAS is a universal DNA sensor, its regulation is crucial in order to avoid any unintended immune responses. While previous research had shown that GAS is enriched inside the nucleus little was known about how cGAS ignores our own healthy DNA. "These findings reshape the current paradigm of cGAS regulation and exemplify the role of the nucleosome in regulating diverse protein functions," concluded McGinty.