Our paper out @CellCellPress: Structure guided discovery of viral proteins that inhibit host immunity Congrats Erez Yirmiya, Azita Leavitt, Gil Amitai, our collaborators at the Kranzusch lab, and coauthors A 🧵 1/10 www.cell.com/cell/abstrac... - ThreadSky

soreklab.bsky.social • 34 days ago

Our paper out @CellCellPress: Structure guided discovery of viral proteins that inhibit host immunity

Congrats Erez Yirmiya, Azita Leavitt, Gil Amitai, our collaborators at the Kranzusch lab, and coauthors

A 🧵 1/10

https://www.cell.com/cell/abstract/S0092-8674(24)01478-8

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soreklab.bsky.social•34 days ago

Many uncharacterized proteins in the viral protein universe are thought to function in host immune inhibition

Using Alphafold (AF), we can now sift through millions of viral proteins for those that bind and inhibit immune proteins

2/10

soreklab.bsky.social•34 days ago

Here, we focused on Thoeris and CBASS, the bacterial immune systems that are the ancestors of eukaryotic TIR and cGAS-STING immunity

We clustered 32M phage proteins, selected 38,700 cluster representatives, and used AF to co-fold each of them with bacterial immune proteins

3/10

soreklab.bsky.social•34 days ago

Phage proteins that received high-confidence AF scores for binding an immune protein were tested experimentally - to see if they can inhibit immunity in vivo and in vitro

4/10

soreklab.bsky.social•34 days ago

We found six families of Thoeris inhibitors and one family of cGAS inhibitors, overall encoded in thousands of phages

Crystal strx of a complex between Thoeris TIR and one of the inhibitors (thank you Kranzusch lab!) completely matched AF prediction (strx in color; prediction grey)

5/10

soreklab.bsky.social•34 days ago

All TIR binders inhibit TIR activity by making direct contacts with the catalytic residue of the TIR active site

6/10

soreklab.bsky.social•34 days ago

Remarkably, we found that Tad4, a phage-encoded anti-Thoeris protein, can also bind and inhibit the plant immune TIR protein BdTIR, as well as the TIR of the human protein SARM1

Conservation of TIRs across bacteria, plants and humans leads to conservation of anti-TIR as well

7/10

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