Target DNA-dependent activation mechanism of the prokaryotic immune system SPARTA

Author:

Finocchio Giada1ORCID,Koopal Balwina2ORCID,Potocnik Ana2ORCID,Heijstek Clint2,Westphal Adrie H2,Jinek Martin1ORCID,Swarts Daan C2ORCID

Affiliation:

1. Department of Biochemistry, University of Zurich , 8057 Zurich , Switzerland

2. Laboratory of Biochemistry, Wageningen University , 6708 WE Wageningen , the Netherlands

Abstract

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 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.

Funder

European Research Council

COMPASS

Dutch Research Council

Publisher

Oxford University Press (OUP)

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