SNAP output for PDB entry 7qqk [SNAP web server]

PDB-id

7qqk; SNAP-derived features in text and JSON formats; DNAproDB

Class

signaling protein

Method

cryo-EM (3.8 Å)

Summary

Tir-saved effector bound to ca3

Reference

Hogrel G, Guild A, Graham S, Rickman H, Gruschow S, Bertrand Q, Spagnolo L, White MF (2022): "Cyclic nucleotide-induced helical structure activates a TIR immune effector." Nature, 608, 808-812. doi: 10.1038/s41586-022-05070-9.

Abstract

Cyclic nucleotide signalling is a key component of antiviral defence in all domains of life. Viral detection activates a nucleotide cyclase to generate a second messenger, resulting in activation of effector proteins. This is exemplified by the metazoan cGAS-STING innate immunity pathway₁, which originated in bacteria₂. These defence systems require a sensor domain to bind the cyclic nucleotide and are often coupled with an effector domain that, when activated, causes cell death by destroying essential biomolecules₃. One example is the Toll/interleukin-1 receptor (TIR) domain, which degrades the essential cofactor NAD₊ when activated in response to infection in plants and bacteria_2,4,5 or during programmed nerve cell death₆. Here we show that a bacterial antiviral defence system generates a cyclic tri-adenylate that binds to a TIR-SAVED effector, acting as the 'glue' to allow assembly of an extended superhelical solenoid structure. Adjacent TIR subunits interact to organize and complete a composite active site, allowing NAD₊ degradation. Activation requires extended filament formation, both in vitro and in vivo. Our study highlights an example of large-scale molecular assembly controlled by cyclic nucleotides and reveals key details of the mechanism of TIR enzyme activation.