Cyclic di-GMP sensing via the innate immune signaling protein STING.
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.
Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA. qiy2001@med.cornell.edu
Qian
Q
Yin
Yuan
Y
Tian
Venkataraman
V
Kabaleeswaran
Xiaomo
X
Jiang
Daqi
D
Tu
Michael J
MJ
Eck
Zhijian J
ZJ
Chen
Hao
H
Wu
D000595:Amino Acid Sequence; D001665:Binding Sites; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D006860:Hydrogen Bonding; D007113:Immunity, Innate; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000276:immunology*; D000099197:STING Protein
D006152:Cyclic GMP; D008565:Membrane Proteins; C532857:STING1 protein, human; D000099197:STING Protein; C062025:bis(3',5')-cyclic diguanylic acid