nucleobase-containing small molecule biosynthetic process / NAD catabolic process / NAD+ nucleosidase activity / signal transduction 類似検索 - 分子機能
SMODS-associated and fused to various effectors / SMODS-associated and fused to various effectors sensor domain / TIR domain / Toll/interleukin-1 receptor homology (TIR) domain / Toll/interleukin-1 receptor homology (TIR) domain superfamily 類似検索 - ドメイン・相同性
Biotechnology and Biological Sciences Research Council (BBSRC)
BB/T004789
英国
European Research Council (ERC)
101018608
英国
Medical Research Council (MRC, United Kingdom)
MC_PC_17135
英国
引用
ジャーナル: Nature / 年: 2022 タイトル: Cyclic nucleotide-induced helical structure activates a TIR immune effector. 著者: Gaëlle Hogrel / Abbie Guild / Shirley Graham / Hannah Rickman / Sabine Grüschow / Quentin Bertrand / Laura Spagnolo / Malcolm F White / 要旨: 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 ...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 pathway, which originated in bacteria. 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 biomolecules. 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 or during programmed nerve cell death. 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.