6ea6

Structure of VACV poxin 2'3' cGAMP-specific nuclease

spinqualitylabelsall models 6ea6, resolution 1.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6ea6 is a 4 chain structure with sequence from Vaccinia virus WR. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.703Å Ligands: MSE Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function POXIN_VACCW Nuclease that is responsible for viral evasion of host cGAS-STING innate immunity (PubMed:30728498). Cleaves 2',3'-cGAMP which is produced by host cGAS following recognition of cytosolic DNA and blocks the subsequent 2',3'-cGAMP-mediated activation of TMEM173/STING, which normally spreads to adjacent cells and activates the interferon and NF-kappa-B immune responses (PubMed:30728498). Publication Abstract from PubMed Cytosolic DNA triggers innate immune responses through the activation of cyclic GMP-AMP synthase (cGAS) and production of the cyclic dinucleotide second messenger 2',3'-cyclic GMP-AMP (cGAMP)(1-4). 2',3'-cGAMP is a potent inducer of immune signalling; however, no intracellular nucleases are known to cleave 2',3'-cGAMP and prevent the activation of the receptor stimulator of interferon genes (STING)(5-7). Here we develop a biochemical screen to analyse 24 mammalian viruses, and identify poxvirus immune nucleases (poxins) as a family of 2',3'-cGAMP-degrading enzymes. Poxins cleave 2',3'-cGAMP to restrict STING-dependent signalling and deletion of the poxin gene (B2R) attenuates vaccinia virus replication in vivo. Crystal structures of vaccinia virus poxin in pre- and post-reactive states define the mechanism of selective 2',3'-cGAMP degradation through metal-independent cleavage of the 3'-5' bond, converting 2',3'-cGAMP into linear Gp[2'-5']Ap[3']. Poxins are conserved in mammalian poxviruses. In addition, we identify functional poxin homologues in the genomes of moths and butterflies and the baculoviruses that infect these insects. Baculovirus and insect host poxin homologues retain selective 2',3'-cGAMP degradation activity, suggesting an ancient role for poxins in cGAS-STING regulation. Our results define poxins as a family of 2',3'-cGAMP-specific nucleases and demonstrate a mechanism for how viruses evade innate immunity. Viral and metazoan poxins are cGAMP-specific nucleases that restrict cGAS-STING signalling.,Eaglesham JB, Pan Y, Kupper TS, Kranzusch PJ Nature. 2019 Feb;566(7743):259-263. doi: 10.1038/s41586-019-0928-6. Epub 2019 Feb, 6. PMID:30728498 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA