Molecular Cell
Volume 46, Issue 6, 29 June 2012, Pages 735-745
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Article
Cyclic di-GMP Sensing via the Innate Immune Signaling Protein STING

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Summary

Detection of foreign materials is the first step of successful immune responses. Stimulator of interferon genes (STING) was shown to directly bind cyclic diguanylate monophosphate (c-di-GMP), a bacterial second messenger, and to elicit strong interferon responses. Here we elucidate the structural features of the cytosolic c-di-GMP binding domain (CBD) of STING and its complex with c-di-GMP. The CBD exhibits an α + β fold and is a dimer in the crystal and in solution. Surprisingly, one c-di-GMP molecule binds to the central crevice of a STING dimer, using a series of stacking and hydrogen bonding interactions. We show that STING is autoinhibited by an intramolecular interaction between the CBD and the C-terminal tail (CTT) and that c-di-GMP releases STING from this autoinhibition by displacing the CTT. The structures provide a remarkable example of pathogen-host interactions in which a unique microbial molecule directly engages the innate immune system.

Highlights

▸ The c-di-GMP binding domain (CBD) of STING is a wing-shaped dimer with a novel fold ▸ c-di-GMP assumes a symmetrical conformation and binds at the STING dimer interface ▸ STING is autoinhibited by an intramolecular interaction which c-di-GMP antagonizes

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