Cyclic GMP-AMP synthase
| Cyclic GMP-AMP synthase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
cGAS complexed with dsDNA (based on PDB 4O6A) | |||||||||
| Identifiers | |||||||||
| EC no. | 2.7.7.86 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| |||||||||
Cyclic GMP-AMP synthase (cGAS, cGAMP synthase), belonging to the nucleotidyltransferase family, is a cytosolic DNA sensor that activates a type-I interferon response. It is part of the cGAS-STING DNA sensing pathway. It binds to microbial DNA as well as self DNA that invades the cytoplasm, and catalyzes cGAMP synthesis. cGAMP then functions as a second messenger that binds to and activates the endoplasmic reticulum protein STING to trigger type-I IFNs production. Mice lacking cGAS are more vulnerable to lethal infection by DNA viruses and RNA viruses. In addition, cGAS has been shown to be an innate immune sensor of retroviruses including HIV. The human gene encoding cGAS is MB21D1 on chromosome 6.
Human cGAS has been shown to produce less 2'3' cGAMP than mouse cGAS . This difference can be explained by the structural differences between mcGAS and hcGAS. Human cGAS is activated in a strongly DNA length-dependent manner . Indeed, human cGAS exhibits a higher affinity for DNA fragments of over 45 bp, whereas mouse cGAS is preferentially activated by shorter DNA sequences. Two amino acids, K187 and L195 in the N-terminus of hcGAS, have been shown to be responsible for human-specific control of 2'3' cGAMP synthesis . The opposing responses of hcGAS and mcGAS to short DNA are completely reversed by the human-specific K187/L195 substitution .