Molecular basis of CD-NTase nucleotide selection in CBASS anti-phage defense

Anonymous — Tue, 01 Jun 2021 06:00:00 +0000

Molecular basis of CD-NTase nucleotide selection in CBASS anti-phage defense Anonymous (not verified) Tue, 06/01/2021 - 00:00

Govande AA , Duncan-Lowey B , Eaglesham JB , ➤Whiteley AT , Kranzusch PJ

Cell Rep. 2021 Jun 1;35(9):109206. doi: 10.1016/j.celrep.2021.109206.

Abstract

cGAS/DncV-like nucleotidyltransferase (CD-NTase) enzymes are signaling proteins that initiate antiviral immunity in animal cells and cyclic-oligonucleotide-based anti-phage signaling system (CBASS) phage defense in bacteria. Upon phage recognition, bacterial CD-NTases catalyze synthesis of cyclic-oligonucleotide signals, which activate downstream effectors and execute cell death. How CD-NTases control nucleotide selection to specifically induce defense remains poorly defined. Here, we combine structural and nucleotide-analog interference-mapping approaches to identify molecular rules controlling CD-NTase specificity. Structures of the cyclic trinucleotide synthase Enterobacter cloacae CdnD reveal coordinating nucleotide interactions and a possible role for inverted nucleobase positioning during product synthesis. We demonstrate that correct nucleotide selection in the CD-NTase donor pocket results in the formation of a thermostable-protein-nucleotide complex, and we extend our analysis to establish specific patterns governing selectivity for each of the major bacterial CD-NTase clades A-H. Our results explain CD-NTase specificity and enable predictions of nucleotide second-messenger signals within diverse antiviral systems.

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Molecular basis of CD-NTase nucleotide selection in CBASS anti-phage defense

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