7LT2

Structure of a dsRNA-sensing cGAS-like receptor from the beetle Tribolium castaneum

Summary for 7LT2

• Entry DOI: 10.2210/pdb7lt2/pdb
• Descriptor: Mab-21 domain-containing protein, MANGANESE (II) ION (3 entities in total)
• Functional Keywords: cgas-like receptor, cglr, nucleotidyltransferase, immune system
• Biological source: Tribolium castaneum (Red flour beetle)
• Total number of polymer chains: 1
• Total formula weight: 46389.00

Authors

Slavik, K.M.,Morehouse, B.R.,Kranzusch, P.J. (deposition date: 2021-02-18, release date: 2021-07-21, Last modification date: 2024-05-22)

Primary citation

Slavik, K.M.,Morehouse, B.R.,Ragucci, A.E.,Zhou, W.,Ai, X.,Chen, Y.,Li, L.,Wei, Z.,Bahre, H.,Konig, M.,Seifert, R.,Lee, A.S.Y.,Cai, H.,Imler, J.L.,Kranzusch, P.J.
cGAS-like receptors sense RNA and control 3'2'-cGAMP signalling in Drosophila.
Nature, 597:109-113, 2021

PubMed Abstract: Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that produces the second messenger cG[2'-5']pA[3'-5']p (2'3'-cGAMP) and controls activation of innate immunity in mammalian cells. Animal genomes typically encode multiple proteins with predicted homology to cGAS, but the function of these uncharacterized enzymes is unknown. Here we show that cGAS-like receptors (cGLRs) are innate immune sensors that are capable of recognizing divergent molecular patterns and catalysing synthesis of distinct nucleotide second messenger signals. Crystal structures of human and insect cGLRs reveal a nucleotidyltransferase signalling core shared with cGAS and a diversified primary ligand-binding surface modified with notable insertions and deletions. We demonstrate that surface remodelling of cGLRs enables altered ligand specificity and used a forward biochemical screen to identify cGLR1 as a double-stranded RNA sensor in the model organism Drosophila melanogaster. We show that RNA recognition activates Drosophila cGLR1 to synthesize the novel product cG[3'-5']pA[2'-5']p (3'2'-cGAMP). A crystal structure of Drosophila stimulator of interferon genes (dSTING) in complex with 3'2'-cGAMP explains selective isomer recognition, and 3'2'-cGAMP induces an enhanced antiviral state in vivo that protects from viral infection. Similar to radiation of Toll-like receptors in pathogen immunity, our results establish cGLRs as a diverse family of metazoan pattern recognition receptors.

PubMed: 34261127
DOI: 10.1038/s41586-021-03743-5

Experimental method

X-RAY DIFFRACTION (1.58 Å)