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Crystal structure and functional implication of bacterial STING.

ABSTRACT: Mammalian innate immune sensor STING (STimulator of INterferon Gene) was recently found to originate from bacteria. During phage infection, bacterial STING sense c-di-GMP generated by the CD-NTase (cGAS/DncV-like nucleotidyltransferase) encoded in the same operon and signal suicide commitment as a defense strategy that restricts phage propagation. However, the precise binding mode of c-di-GMP to bacterial STING and the specific recognition mechanism are still elusive. Here, we determine two complex crystal structures of bacterial STING/c-di-GMP, which provide a clear picture of how c-di-GMP is distinguished from other cyclic dinucleotides. The protein-protein interactions further reveal the driving force behind filament formation of bacterial STING. Finally, we group the bacterial STING into two classes based on the conserved motif in β-strand lid, which dictate their ligand specificity and oligomerization mechanism, and propose an evolution-based model that describes the transition from c-di-GMP-dependent signaling in bacteria to 2'3'-cGAMP-dependent signaling in eukaryotes.

SUBMITTER: Ko TP

PROVIDER: S-EPMC8748872 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Crystal structure and functional implication of a bacterial cyclic AMP-AMP-GMP synthetase.

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Cryo-EM structure of an active bacterial TIR-STING filament complex.

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Crystal structure of human NLRP12 PYD domain and implication in homotypic interaction.

Project description:NLRP12 is a NOD-like receptor that plays multiple roles in both inflammation and tumorigenesis. Despite the importance, little is known about its mechanism of action at the molecular level. Here, we report the crystal structure of NLRP12 PYD domain at 1.70 Å fused with an maltose-binding protein (MBP) tag. Interestingly, the PYD domain forms a dimeric configuration through a disulfide bond in the crystal. The possible biological significance is discussed in the context of ROS induced NF-?B activation.

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Crystal structure of a bacterial ribonuclease P RNA.

Project description:The x-ray crystal structure of a 417-nt ribonuclease P RNA from Bacillus stearothermophilus was solved to 3.3-A resolution. This RNA enzyme is constructed from a number of coaxially stacked helical domains joined together by local and long-range interactions. These helical domains are arranged to form a remarkably flat surface, which is implicated by a wealth of biochemical data in the binding and cleavage of the precursors of transfer RNA substrate. Previous photoaffinity crosslinking data are used to position the substrate on the crystal structure and to identify the chemically active site of the ribozyme. This site is located in a highly conserved core structure formed by intricately interlaced long-range interactions between interhelical sequences.

| S-EPMC1224664 | biostudies-literature

Crystal structure of the bacterial nucleoside transporter Tsx.

Project description:Tsx is a nucleoside-specific outer membrane (OM) transporter of Gram-negative bacteria. We present crystal structures of Escherichia coli Tsx in the absence and presence of nucleosides. These structures provide a mechanism for nucleoside transport across the bacterial OM. Tsx forms a monomeric, 12-stranded beta-barrel with a long and narrow channel spanning the outer membrane. The channel, which is shaped like a keyhole, contains several distinct nucleoside-binding sites, two of which are well defined. The base moiety of the nucleoside is located in the narrow part of the keyhole, while the sugar occupies the wider opening. Pairs of aromatic residues and flanking ionizable residues are involved in nucleoside binding. Nucleoside transport presumably occurs by diffusion from one binding site to the next.

| S-EPMC514505 | biostudies-literature

Crystal structure of a chimaeric bacterial glutamate dehydrogenase.

Project description:Glutamate dehydrogenases (EC 1.4.1.2-4) catalyse the oxidative deamination of L-glutamate to α-ketoglutarate using NAD(P)(+) as a cofactor. The bacterial enzymes are hexameric, arranged with 32 symmetry, and each polypeptide consists of an N-terminal substrate-binding segment (domain I) followed by a C-terminal cofactor-binding segment (domain II). The catalytic reaction takes place in the cleft formed at the junction of the two domains. Distinct signature sequences in the nucleotide-binding domain have been linked to the binding of NAD(+) versus NADP(+), but they are not unambiguous predictors of cofactor preference. In the absence of substrate, the two domains move apart as rigid bodies, as shown by the apo structure of glutamate dehydrogenase from Clostridium symbiosum. Here, the crystal structure of a chimaeric clostridial/Escherichia coli enzyme has been determined in the apo state. The enzyme is fully functional and reveals possible determinants of interdomain flexibility at a hinge region following the pivot helix. The enzyme retains the preference for NADP(+) cofactor from the parent E. coli domain II, although there are subtle differences in catalytic activity.

| S-EPMC4909246 | biostudies-literature

Crystal structure of Fc? receptor I and its implication in high affinity ?-immunoglobulin binding.

Project description:Fc? receptors (Fc?Rs) play critical roles in humoral and cellular immune responses through interactions with the Fc region of immunoglobulin G (IgG). Among them, Fc?RI is the only high affinity receptor for IgG and thus is a potential target for immunotherapy. Here we report the first crystal structure of an Fc?RI with all three extracellular Ig-like domains (designated as D1, D2, and D3). The structure shows that, first, Fc?RI has an acute D1-D2 hinge angle similar to that of Fc?RI but much smaller than those observed in the low affinity Fc? receptors. Second, the D3 domain of Fc?RI is positioned away from the putative IgG binding site on the receptor and is thus unlikely to make direct contacts with Fc. Third, the replacement of Fc?RIII FG-loop ((171)LVGSKNV(177)) with that of Fc?RI ((171)MGKHRY(176)) resulted in a 15-fold increase in IgG(1) binding affinity, whereas a valine insertion in the Fc?RI FG-loop ((171)MVGKHRY(177)) abolished the affinity enhancement. Thus, the Fc?RI FG-loop with its conserved one-residue deletion is critical to the high affinity IgG binding. The structural results support Fc?RI binding to IgG in a similar mode as its low affinity counterparts. Taken together, our study suggests a molecular mechanism for the high affinity IgG recognition by Fc?RI and provides a structural basis for understanding its physiological function and its therapeutic implication in treating autoimmune diseases.

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Project description: Not available

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Crystal structure of the bacterial cell division inhibitor MinC.

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| S-EPMC125452 | biostudies-literature

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