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| Title | Target DNA-dependent activation mechanism of the prokaryotic immune system SPARTA. |
|---|---|
| Journal, issue, pages | Nucleic Acids Res, Vol. 52, Issue 4, Page 2012-2029, Year 2024 |
| Publish date | Feb 28, 2024 |
 Authors | Giada Finocchio / Balwina Koopal / Ana Potocnik / Clint Heijstek / Adrie H Westphal / Martin Jinek / Daan C Swarts /   |
| PubMed Abstract | In both prokaryotic and eukaryotic innate immune systems, TIR domains function as NADases that degrade the key metabolite NAD+ or generate signaling molecules. Catalytic activation of TIR domains ...In both prokaryotic and eukaryotic innate immune systems, TIR domains function as NADases that degrade the key metabolite NAD+ or generate signaling molecules. Catalytic activation of TIR domains requires oligomerization, but how this is achieved varies in distinct immune systems. In the Short prokaryotic Argonaute (pAgo)/TIR-APAZ (SPARTA) immune system, TIR NADase activity is triggered upon guide RNA-mediated recognition of invading DNA by an unknown mechanism. Here, we describe cryo-EM structures of SPARTA in the inactive monomeric and target DNA-activated tetrameric states. The monomeric SPARTA structure reveals that in the absence of target DNA, a C-terminal tail of TIR-APAZ occupies the nucleic acid binding cleft formed by the pAgo and TIR-APAZ subunits, inhibiting SPARTA activation. In the active tetrameric SPARTA complex, guide RNA-mediated target DNA binding displaces the C-terminal tail and induces conformational changes in pAgo that facilitate SPARTA-SPARTA dimerization. Concurrent release and rotation of one TIR domain allow it to form a composite NADase catalytic site with the other TIR domain within the dimer, and generate a self-complementary interface that mediates cooperative tetramerization. Combined, this study provides critical insights into the structural architecture of SPARTA and the molecular mechanism underlying target DNA-dependent oligomerization and catalytic activation. |
 External links | Nucleic Acids Res / PubMed:38224450 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.57 - 3.14 Å |
| Structure data | EMDB-18486, PDB-8qlo: EMDB-18487, PDB-8qlp: |
| Chemicals |  ChemComp-MG: |
| Source |
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 Keywords | IMMUNE SYSTEM / Prokaryotic Argonaute / TIR domain / RNA binding protein / DNA binding protein / Oligomerization / NADase activity |
bacillales bacterium (bacteria)