Novel Mechanism for Cyclic Dinucleotide Degradation Revealed by Structural Studies of Vibrio Phosphodiesterase V-cGAP3 |
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Authors: | Ming-jing Deng Jianli Tao Chao E Zhao-yang Ye Zhengfan Jiang Jin Yu Xiao-dong Su |
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Institution: | 1. State Key Laboratory of Protein and Plant Gene Research, and Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China;2. Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing 100871, China;3. Peking-Tsinghua Center for Life Sciences, Beijing, China;4. Beijing Computational Science Research Center, Beijing 100193, China;5. Clinical Research Center, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, China |
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Abstract: | 3′3′-cyclic GMP–AMP (3′3′-cGAMP) belongs to a family of the bacterial secondary messenger cyclic dinucleotides. It was first discovered in the Vibrio cholerae seventh pandemic strains and is involved in efficient intestinal colonization and chemotaxis regulation. Phosphodiesterases (PDEs) that degrade 3′3′-cGAMP play important regulatory roles in the relevant signaling pathways, and a previous study has identified three PDEs in V. cholerae, namely, V-cGAP1, V-cGAP2, and V-cGAP3, functioning in 3′3′-cGAMP degradation. We report the crystal structure, biochemical, and structural analyses of V-cGAP3, providing a foundation for understanding the mechanism of 3′3′-cGAMP degradation and regulation in general. Our crystal and molecular dynamic (MD)-simulated structures revealed that V-cGAP3 contains tandem HD-GYP domains within its N- and C-terminal domains, with similar three-dimensional topologies despite their low-sequence identity. Biochemical and structural analyses showed that the N-terminal domain plays a mechanism of positive regulation for the catalytic C-terminal domain. We also demonstrated that the other homologous Vibrio PDEs, V-cGAP1/2, likely function via a similar mechanism. |
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Keywords: | 3′3′-cGAMP 3′3′-cyclic GMP–AMP CDNs cyclic dinucleotides PDEs phosphodiesterases MD molecular dynamic c-di-GMP cyclic di-GMP c-di-AMP cyclic di-AMP 2′3′-cGAMP 2′3′-cyclic GMP–AMP HD His-Asp GYP Gly-Tyr-Pro DHH Asp-His-His N-domain N-terminal domain C-domain C-terminal domain HPLC high-performance liquid chromatography 3′3′-cGAMP phosphodiesterase crystal structure molecular dynamics simulation bi-nuclear metal center |
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