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-Structure paper
タイトル | Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP-AMP. |
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ジャーナル・号・ページ | Nature, Vol. 567, Issue 7748, Page 389-393, Year 2019 |
掲載日 | 2019年3月6日 |
著者 | Guijun Shang / Conggang Zhang / Zhijian J Chen / Xiao-Chen Bai / Xuewu Zhang / |
PubMed 要旨 | 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 ...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). STING is an endoplasmic-reticulum membrane protein that contains four transmembrane helices followed by a cytoplasmic ligand-binding and signalling domain. The cytoplasmic domain of STING forms a dimer, which undergoes a conformational change upon binding to cGAMP. 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. |
リンク | Nature / PubMed:30842659 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 4.0 - 6.5 Å |
構造データ | EMDB-0502, PDB-6nt5: EMDB-0503, PDB-6nt6: |
化合物 | ChemComp-1SY: |
由来 |
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キーワード | IMMUNE SYSTEM / ER / membrane / adaptor |