Finally, a note on TVC. We've released tvc.apps.aithyra.at to enable exploration by the community. Here, for most viral proteins you can see domain-level annotations at the sequence and structure level. You can also chat with an AI about the database, and do seq/struc searches against TVC 12/15

We found that dsRBDs are widespread in the viral proteome, and that diverse eukaryotic viral and phage dsRBDs can restrict dsRNA-sensing in human cells! So, the dsRBD fold is another recurrently-adapted structural feature involved in pan-viral immune antagonism. 10/15

Next, we looked at the double-stranded RNA binding domain (dsRBD) fold, which is used by some eukaryotic RNA viruses to evade human dsRNA-sensing pathways. Curiously, the phage protein Acb4, which inhibits cGAS-like enzymes by sequestering cGAMP, is also an adapted dsRBD. So, we dug in. 9/15

We found that viral DHH and HD-GYP PDEs can degrade 3'3' cGAMP, and can suppress cGAMP-mediated STING activation in human cells. This suggests that PDE folds capable of immune antagonism are widespread, and shows a fascinating connection between cGAMP regulation by bacterial and viral pathogens 8/15

Protein structure searches revealed several viral HD-GYP and a large number of viral DHH PDEs. Phylogenetic analyses revealed evidence of pervasive horizontal gene transfer of DHH PDEs, often from bacteria to bacterial viruses. DHH PDEs are also present in some mimiviruses that infect amoeba 7/15

Next, we investigated folds capable of immune antagonism. To start, we took inspiration from bacterial pathogens. M. tuberculosis encodes the DHH-family PDE CdnP to degrade human 2'3' cGAMP, while V. cholerae encodes the HD-GYP family PDEs called v-cGAPs to regulate bacterial 3'3'-cGAMP levels 6/15

With this domain-level information, we also could systematically assess how domains co-occur. Using this method, we identified a diverse and widespread family of multi-domain viral proteins reconstituting the Mre11-Rad50 multiprotein complex involved in cellular DNA repair 5/15

We separated these proteins into 790K distinct protein domains and systematically mapped their relationships and potential annotations. We found that protein structure alignments give putative annotations for 88% of well-folded domains (compared to 12% with sequence methods!) 4/15

We previously found that viral 2H phosphodiesterases (PDEs) are used by both animal and bacterial viruses to degrade cGAMP, a messenger made by cGAS-like enzymes in bacterial and animal immunity. Here, we asked the question: Are other folds recurrently reused by pathogens for immune antagonism? 2/15

Hello everyone! I am pleased to share information on the first ever Computational Structural Virology Symposium, conducted August 4th on zoom and highlighting work in this emerging field. You can register for this event here: forms.gle/CNiqskMwQEuV.... Please re-post!