Abstract
Infections by pathogens that contain DNA trigger the production of type-I interferons and inflammatory cytokines through cyclic GMP–AMP synthase, which produces 2′3′-cyclic GMP–AMP (cGAMP) that binds to and activates stimulator of interferon genes (STING; also known as TMEM173, MITA, ERIS and MPYS) 1–8 . STING is an endoplasmic-reticulum membrane protein that contains four transmembrane helices followed by a cytoplasmic ligand-binding and signalling domain 9–13 . The cytoplasmic domain of STING forms a dimer, which undergoes a conformational change upon binding to cGAMP 9,14 . However, it remains unclear how this conformational change leads to STING activation. Here we present cryo-electron microscopy structures of full-length STING from human and chicken in the inactive dimeric state (about 80 kDa in size), as well as cGAMP-bound chicken STING in both the dimeric and tetrameric states. The structures show that the transmembrane and cytoplasmic regions interact to form an integrated, domain-swapped dimeric assembly. Closure of the ligand-binding domain, induced by cGAMP, leads to a 180° rotation of the ligand-binding domain relative to the transmembrane domain. This rotation is coupled to a conformational change in a loop on the side of the ligand-binding-domain dimer, which leads to the formation of the STING tetramer and higher-order oligomers through side-by-side packing. This model of STING oligomerization and activation is supported by our structure-based mutational analyses.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 389-393 |
| Number of pages | 5 |
| Journal | Nature |
| Volume | 567 |
| Issue number | 7748 |
| DOIs | |
| State | Published - Mar 21 2019 |
Fingerprint
ASJC Scopus subject areas
- General
Cite this
Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP–AMP. / Shang, Guijun; Zhang, Conggang; Chen, Zhijian; Bai, Xiaochen; Zhang, Xuewu.
In: Nature, Vol. 567, No. 7748, 21.03.2019, p. 389-393.Research output: Contribution to journal › Letter
}
TY - JOUR
T1 - Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP–AMP
AU - Shang, Guijun
AU - Zhang, Conggang
AU - Chen, Zhijian
AU - Bai, Xiaochen
AU - Zhang, Xuewu
PY - 2019/3/21
Y1 - 2019/3/21
N2 - Infections by pathogens that contain DNA trigger the production of type-I interferons and inflammatory cytokines through cyclic GMP–AMP synthase, which produces 2′3′-cyclic GMP–AMP (cGAMP) that binds to and activates stimulator of interferon genes (STING; also known as TMEM173, MITA, ERIS and MPYS) 1–8 . STING is an endoplasmic-reticulum membrane protein that contains four transmembrane helices followed by a cytoplasmic ligand-binding and signalling domain 9–13 . The cytoplasmic domain of STING forms a dimer, which undergoes a conformational change upon binding to cGAMP 9,14 . However, it remains unclear how this conformational change leads to STING activation. Here we present cryo-electron microscopy structures of full-length STING from human and chicken in the inactive dimeric state (about 80 kDa in size), as well as cGAMP-bound chicken STING in both the dimeric and tetrameric states. The structures show that the transmembrane and cytoplasmic regions interact to form an integrated, domain-swapped dimeric assembly. Closure of the ligand-binding domain, induced by cGAMP, leads to a 180° rotation of the ligand-binding domain relative to the transmembrane domain. This rotation is coupled to a conformational change in a loop on the side of the ligand-binding-domain dimer, which leads to the formation of the STING tetramer and higher-order oligomers through side-by-side packing. This model of STING oligomerization and activation is supported by our structure-based mutational analyses.
AB - Infections by pathogens that contain DNA trigger the production of type-I interferons and inflammatory cytokines through cyclic GMP–AMP synthase, which produces 2′3′-cyclic GMP–AMP (cGAMP) that binds to and activates stimulator of interferon genes (STING; also known as TMEM173, MITA, ERIS and MPYS) 1–8 . STING is an endoplasmic-reticulum membrane protein that contains four transmembrane helices followed by a cytoplasmic ligand-binding and signalling domain 9–13 . The cytoplasmic domain of STING forms a dimer, which undergoes a conformational change upon binding to cGAMP 9,14 . However, it remains unclear how this conformational change leads to STING activation. Here we present cryo-electron microscopy structures of full-length STING from human and chicken in the inactive dimeric state (about 80 kDa in size), as well as cGAMP-bound chicken STING in both the dimeric and tetrameric states. The structures show that the transmembrane and cytoplasmic regions interact to form an integrated, domain-swapped dimeric assembly. Closure of the ligand-binding domain, induced by cGAMP, leads to a 180° rotation of the ligand-binding domain relative to the transmembrane domain. This rotation is coupled to a conformational change in a loop on the side of the ligand-binding-domain dimer, which leads to the formation of the STING tetramer and higher-order oligomers through side-by-side packing. This model of STING oligomerization and activation is supported by our structure-based mutational analyses.
UR - http://www.scopus.com/inward/record.url?scp=85063003311&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85063003311&partnerID=8YFLogxK
U2 - 10.1038/s41586-019-0998-5
DO - 10.1038/s41586-019-0998-5
M3 - Letter
C2 - 30842659
AN - SCOPUS:85063003311
VL - 567
SP - 389
EP - 393
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7748
ER -