Crystal structures of STING protein reveal basis for recognition of cyclic di-GMP

Shang, Guijun; Zhu, Deyu; Li, Ning; Zhang, Junbing; Zhu, Chunyuan; Lu, Defen; Liu, Cuilan; Qian, Yu; Zhao, Yanyu; Xu, Sujuan; Gu, Lichuan

doi:10.1038/nsmb.2332

Cited by 196 publications

(165 citation statements)

References 27 publications

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“…In all structures, as well as in solution, apo-STING adopts a homodimeric V-shaped fold. It harbors a deep central cleft, which is lined by the kinked α1 helices and accommodates the long and mostly unstructured β2-β3 loops of each subunit 88,91,93–95 . While dimerization is mainly mediated by conserved hydrophobic interactions involving N-proximal residues of α1 and part of α3, the dimer exhibits significant conformational variations among solved apo-structures.…”

Section: Eukaryotic Sensing Through Stingmentioning

confidence: 99%

Versatile modes of cellular regulation via cyclic dinucleotides

2017

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Since the discovery of c-di-GMP almost three decades ago, cyclic dinucleotides (CDNs) have emerged as widely used signaling molecules in most kingdoms of life. The family of second messengers now includes c-di-AMP and distinct versions of mixed cyclic GMP-AMP (cGAMP) compounds. Along with these nucleotides, a vast number of proteins for the production and turnover of these molecules have been described, as well as effectors that translate the signals into physiological responses. The latter include but are not limited to mechanisms for adaptation and survival in prokaryotes, persistence and virulence of bacterial pathogens, as well as immune responses to viral and bacterial invasion in eukaryotes. In this review we will focus on recent discoveries and emerging themes that illustrate the ubiquity and versatility of cyclic dinucleotide function at the transcriptional and post-translational levels and, in particular, on insights gained through mechanistic structure-function analyses.

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Section: Eukaryotic Sensing Through Stingmentioning

confidence: 99%

Versatile modes of cellular regulation via cyclic dinucleotides

2017

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“…STING binds c-di-GMP with a K D of 5 M and stimulates production of type I interferons by signaling through the TANK binding kinase 1 (TBK1) and the interferon regulatory transcription factor 3 (IRF3) (69). At least five groups have solved the crystal structure of STING (70,72,73,177,421) in complex with c-di-GMP (Fig. 5G).…”

Section: Cyclic Di-gmp As An Immunomodulatormentioning

confidence: 99%

Cyclic di-GMP: the First 25 Years of a Universal Bacterial Second Messenger

Römling

Galperin

Gomelsky

2013

Microbiol Mol Biol Rev

1,500

1,698

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SUMMARY Twenty-five years have passed since the discovery of cyclic dimeric (3′→5′) GMP (cyclic di-GMP or c-di-GMP). From the relative obscurity of an allosteric activator of a bacterial cellulose synthase, c-di-GMP has emerged as one of the most common and important bacterial second messengers. Cyclic di-GMP has been shown to regulate biofilm formation, motility, virulence, the cell cycle, differentiation, and other processes. Most c-di-GMP-dependent signaling pathways control the ability of bacteria to interact with abiotic surfaces or with other bacterial and eukaryotic cells. Cyclic di-GMP plays key roles in lifestyle changes of many bacteria, including transition from the motile to the sessile state, which aids in the establishment of multicellular biofilm communities, and from the virulent state in acute infections to the less virulent but more resilient state characteristic of chronic infectious diseases. From a practical standpoint, modulating c-di-GMP signaling pathways in bacteria could represent a new way of controlling formation and dispersal of biofilms in medical and industrial settings. Cyclic di-GMP participates in interkingdom signaling. It is recognized by mammalian immune systems as a uniquely bacterial molecule and therefore is considered a promising vaccine adjuvant. The purpose of this review is not to overview the whole body of data in the burgeoning field of c-di-GMP-dependent signaling. Instead, we provide a historic perspective on the development of the field, emphasize common trends, and illustrate them with the best available examples. We also identify unresolved questions and highlight new directions in c-di-GMP research that will give us a deeper understanding of this truly universal bacterial second messenger.

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“…One such noncanonical binding mode is found in the mammalian STING protein that senses bacterial c-di-GMP to elicit the innate immune response. Several human and mouse STING structures in complex with c-di-GMP have been reported (50)(51)(52)(53)(54), all with a single c-di-GMP binding at the interface of the STING dimer in a symmetrical way (Fig. 5A).…”

Section: C-di-gmp At Protein-protein Interfacesmentioning

confidence: 99%

Diversity of Cyclic Di-GMP-Binding Proteins and Mechanisms

2016

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Cyclic di-GMP (c-di-GMP) synthetases and hydrolases (GGDEF, EAL, and HD-GYP domains) can be readily identified in bacterial genome sequences by using standard bioinformatic tools. In contrast, identification of c-di-GMP receptors remains a difficult task, and the current list of experimentally characterized c-di-GMP-binding proteins is likely incomplete. Several classes of c-di-GMP-binding proteins have been structurally characterized; for some others, the binding sites have been identified; and for several potential c-di-GMP receptors, the binding sites remain to be determined. We present here a comparative structural analysis of c-di-GMP-protein complexes that aims to discern the common themes in the binding mechanisms that allow c-di-GMP receptors to bind it with (sub)micromolar affinities despite the 1,000-fold excess of GTP. The available structures show that most receptors use their Arg and Asp/Glu residues to bind c-di-GMP monomers, dimers, or tetramers with stacked guanine bases. The only exception is the EAL domains that bind c-di-GMP monomers in an extended conformation. We show that in c-di-GMPbinding signature motifs, Arg residues bind to the O-6 and N-7 atoms at the Hoogsteen edge of the guanine base, while Asp/Glu residues bind the N-1 and N-2 atoms at its Watson-Crick edge. In addition, Arg residues participate in stacking interactions with the guanine bases of c-di-GMP and the aromatic rings of Tyr and Phe residues. This may account for the presence of Arg residues in the active sites of every receptor protein that binds stacked c-di-GMP. We also discuss the implications of these structural data for the improved understanding of the c-di-GMP signaling mechanisms.

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Crystal structures of STING protein reveal basis for recognition of cyclic di-GMP

Cited by 196 publications

References 27 publications

Versatile modes of cellular regulation via cyclic dinucleotides

Versatile modes of cellular regulation via cyclic dinucleotides

Cyclic di-GMP: the First 25 Years of a Universal Bacterial Second Messenger

Diversity of Cyclic Di-GMP-Binding Proteins and Mechanisms

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