4MKP

Crystal structure of human cGAS apo form

Summary for 4MKP

• Entry DOI: 10.2210/pdb4mkp/pdb
• Descriptor: Cyclic GMP-AMP synthase, ZINC ION (3 entities in total)
• Functional Keywords: nucleotidyltransferase, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm, cytosol: Q8N884
• Total number of polymer chains: 1
• Total formula weight: 42614.45

Authors

Kato, K.,Ishii, R.,Ishitani, R.,Nureki, O. (deposition date: 2013-09-05, release date: 2013-10-30, Last modification date: 2023-11-08)

Primary citation

Kato, K.,Ishii, R.,Goto, E.,Ishitani, R.,Tokunaga, F.,Nureki, O.
Structural and Functional Analyses of DNA-Sensing and Immune Activation by Human cGAS
Plos One, 8:e76983-e76983, 2013

PubMed Abstract: The detection of cytosolic DNA, derived from pathogens or host cells, by cytosolic receptors is essential for appropriate host immune responses. Cyclic GMP-AMP synthase (cGAS) is a newly identified cytosolic DNA receptor that produces cyclic GMP-AMP, which activates stimulator of interferon genes (STING), resulting in TBK1-IRF3 pathway activation followed by the production of type I interferons. Here we report the crystal structure of human cGAS. The structure revealed that a cluster of lysine and arginine residues forms the positively charged DNA binding surface of human cGAS, which is important for the STING-dependent immune activation. A structural comparison with other previously determined cGASs and our functional analyses suggested that a conserved zinc finger motif and a leucine residue on the DNA binding surface are crucial for the DNA-specific immune response of human cGAS, consistent with previous work. These structural features properly orient the DNA binding to cGAS, which is critical for DNA-induced cGAS activation and STING-dependent immune activation. Furthermore, we showed that the cGAS-induced activation of STING also involves the activation of the NF-κB and IRF3 pathways. Our results indicated that cGAS is a DNA sensor that efficiently activates the host immune system by inducing two distinct pathways.

PubMed: 24116191
DOI: 10.1371/journal.pone.0076983

Experimental method

X-RAY DIFFRACTION (1.953 Å)