Structural biology of vertebrate cGAS/Mab21 proteins and their ligand complexes

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Cyclic GMP AMP synthase (cGAS) is an innate immune pattern recognition receptor for cytosolic DNA, detecting e.g. infections by intracellular bacteria, retroviruses, or DNA-viruses. cGAS belongs together with Mab21 proteins to a recently identified family of nucleotidyl transferases (Mab21/cGAS family) that seem to play a role in early cell fate decisions. While, the activity and cellular function of other Mab21 proteins is unknown, cGAS produces the second messenger cyclic GMP AMP (cGAMP) that triggers the type I interferon response by binding to the adaptor and cyclic dinucleotide sensor stimulator of interferon genes STING. Available structural and functional data fail to explain how cGAS is activated by physiologically immune-stimulatory ligands such as >45 base pair DNA. In the proposed research, we will use structural, biochemical and cell based assays to 1) reveal how cGAS is activated by immune-stimulatory ligands and 2) reveal the cellular ligands and enzymatic activity of the sequence related Mab21 proteins. The anticipated results will provide a structural and mechanistic framework to understand the biology, pathology and evolution of a new enzyme family of nucleotidyl-transferases that are key players in innate immune and developmental cell fate decisions.