Target DNA-dependent activation mechanism of the prokaryotic immune system SPARTA
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.
Main Authors: | Finocchio, Giada, Koopal, Balwina, Potocnik, Ana, Heijstek, Clint, Westphal, Adrie H., Jinek, Martin, Swarts, Daan C. |
---|---|
Format: | Article/Letter to editor biblioteca |
Language: | English |
Subjects: | Life Science, |
Online Access: | https://research.wur.nl/en/publications/target-dna-dependent-activation-mechanism-of-the-prokaryotic-immu |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
Similar Items
-
Target DNA-dependent activation mechanism of the prokaryotic immune system SPARTA
by: Finocchio, Giada, et al. -
Prokaryotic Argonautes Function beyond Immunity by Unlinking Replicating Chromosomes
by: Swarts, Daan C. -
Short prokaryotic Argonaute system repurposed as a nucleic acid detection tool
by: Potocnik, Ana, et al. -
Argonaute-based nucleic acid detection system
by: Swarts, Daniël Christianus, et al. -
SPARTA-related RNA and DNA
by: Koopal, Balwina, et al.