Structural studies of integral membrane proteins involved in cellular signaling
Besides RTKs and ion channels, we are also interested in studying other types of integral transmembrane proteins that play critical roles in cellular signaling, such as STING. The cGAS-cGAMP-STING pathway is a universal mechanism for different type of cells to fight microbial infection. As STING is a small membrane protein having a molecular weight of only ~80 kDa, using cryo-EM to solve the structure of this size of membrane protein is a major challenge. Through the collaboration with Xuewu Zhang and James Chen labs, we determined the high resolution structures of full-length STING with and without cGAMP bound, as well as in the higher order oligomeric state, by using the Volta phase plate. These three STING structures in different states provide some intriguing clues about how the conformational change of STING upon CGAMP binding trigger STING oligomerization and activation. We also determined the structure of STING in complex with TBK1, a kinase which can phosphorylate STING to trigger the downstream signaling. The model reveals that a TBK1 dimer is located on top of the STING dimer, through the binding with the C-terminal tail of STING. These structural information, together with biochemical and cellular based analysis, leads us to understand why the recruitment of multiple TBK1 dimers by STING higher order oligomers is critical for STING activation. We are currently working on the structural determination of STING in complex with other binding partners and small drugs.
Xuewu Zhang, James “Zhijian” Chen
Guijun Shang*, Conggang Zhang*, Zhijian J. Chen†, Xiao-chen Bai†, and Xuewu Zhang†. Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP-AMP. Nature volume 567, pages 389–393 (2019).[DOI]
Conggang Zhang*, Guijun Shang*, Xiang Gui, Xuewu Zhang†, Xiao-chen Bai†, and Zhijian J. Chen†. Structural basis of STING binding with and phosphorylation by TBK1. Nature volume 567, pages 394–398 (2019).[DOI]
Xiao-chen Bai, Eeson Rajendra, Guanghui Yang, Yigong Shi†, Sjors Scheres†. Sampling the conformational space of the catalytic subunit of human γ-secretase. eLife 2015;4:e11182.[DOI]
Xiao-chen Bai*†, Chuangye Yan*, Guanghui Yang*, Peilong Lu, Dan Ma, Linfeng Sun, Rui Zhou, Sjors H.W. Scheres†, Yigong Shi†. An atomic structure of human γ-secretase. Nature volume 525, pages 212–217 (10 September 2015).[DOI]
Peilong Lu*, Xiao-chen Bai*, Dan Ma*, Tian Xie, Chuangye Yan, Linfeng Sun, Guanghui Yang, Yanyu Zhao, Rui Zhou, Sjors H. W. Scheres†, Yigong Shi†. Three-dimensional structure of human γ-secretase. Nature volume 512, pages 166–170 (14 August 2014).[DOI]