| Structural highlights
Function
[CAP12_SPHFK] CBASS (cyclic oligonucleotide-based antiphage signaling system) provides immunity against bacteriophage. The CD-NTase protein synthesizes cyclic nucleotides in response to infection; these serve as specific second messenger signals. The signals activate a diverse range of effectors, leading to bacterial cell death and thus abortive phage infection. A type I-D(GG) CBASS system (PubMed:32839535).[1] [2] The effector protein for this CBASS system. Upon activation by c-di-GMP forms filaments which hydrolyze NAD(+); filament formation is required for enzyme activation. Induction in an E.coli strain that synthesizes c-di-GMP leads to significant growth inhibition. Binds c-di-GMP and 3'3'-cGAMP (3'3'-cyclic GMP-AMP), but not c-di-AMP, 2'3'-cGAMP or cUMP-AMP.[3]
Publication Abstract from PubMed
Stimulator of interferon genes (STING) is an antiviral signalling protein that is broadly conserved in both innate immunity in animals and phage defence in prokaryotes(1-4). Activation of STING requires its assembly into an oligomeric filament structure through binding of a cyclic dinucleotide(4-13), but the molecular basis of STING filament assembly and extension remains unknown. Here we use cryogenic electron microscopy to determine the structure of the active Toll/interleukin-1 receptor (TIR)-STING filament complex from a Sphingobacterium faecium cyclic-oligonucleotide-based antiphage signalling system (CBASS) defence operon. Bacterial TIR-STING filament formation is driven by STING interfaces that become exposed on high-affinity recognition of the cognate cyclic dinucleotide signal c-di-GMP. Repeating dimeric STING units stack laterally head-to-head through surface interfaces, which are also essential for human STING tetramer formation and downstream immune signalling in mammals(5). The active bacterial TIR-STING structure reveals further cross-filament contacts that brace the assembly and coordinate packing of the associated TIR NADase effector domains at the base of the filament to drive NAD(+) hydrolysis. STING interface and cross-filament contacts are essential for cell growth arrest in vivo and reveal a stepwise mechanism of activation whereby STING filament assembly is required for subsequent effector activation. Our results define the structural basis of STING filament formation in prokaryotic antiviral signalling.
Cryo-EM structure of an active bacterial TIR-STING filament complex.,Morehouse BR, Yip MCJ, Keszei AFA, McNamara-Bordewick NK, Shao S, Kranzusch PJ Nature. 2022 Jul 20. pii: 10.1038/s41586-022-04999-1. doi:, 10.1038/s41586-022-04999-1. PMID:35859168[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Millman A, Melamed S, Amitai G, Sorek R. Diversity and classification of cyclic-oligonucleotide-based anti-phage signalling systems. Nat Microbiol. 2020 Dec;5(12):1608-1615. doi: 10.1038/s41564-020-0777-y. Epub, 2020 Aug 24. PMID:32839535 doi:http://dx.doi.org/10.1038/s41564-020-0777-y
- ↑ Morehouse BR, Govande AA, Millman A, Keszei AFA, Lowey B, Ofir G, Shao S, Sorek R, Kranzusch PJ. STING cyclic dinucleotide sensing originated in bacteria. Nature. 2020 Sep 2. pii: 10.1038/s41586-020-2719-5. doi:, 10.1038/s41586-020-2719-5. PMID:32877915 doi:http://dx.doi.org/10.1038/s41586-020-2719-5
- ↑ Morehouse BR, Govande AA, Millman A, Keszei AFA, Lowey B, Ofir G, Shao S, Sorek R, Kranzusch PJ. STING cyclic dinucleotide sensing originated in bacteria. Nature. 2020 Sep 2. pii: 10.1038/s41586-020-2719-5. doi:, 10.1038/s41586-020-2719-5. PMID:32877915 doi:http://dx.doi.org/10.1038/s41586-020-2719-5
- ↑ Morehouse BR, Yip MCJ, Keszei AFA, McNamara-Bordewick NK, Shao S, Kranzusch PJ. Cryo-EM structure of an active bacterial TIR-STING filament complex. Nature. 2022 Jul 20. pii: 10.1038/s41586-022-04999-1. doi:, 10.1038/s41586-022-04999-1. PMID:35859168 doi:http://dx.doi.org/10.1038/s41586-022-04999-1
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