Novel Mechanism for Cyclic Dinucleotide Degradation Revealed by Structural Studies of Vibrio Phosphodiesterase V-cGAP3

Novel Mechanism for Cyclic Dinucleotide Degradation Revealed by Structural Studies of Vibrio Phosphodiesterase V-cGAP3

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. (C) 2018 Published by Elsevier Ltd.

3'3'-环鸟苷酸 - 腺苷酸（3'3'-cGAMP）属于细菌第二信使环二核苷酸家族。它首次在霍乱弧菌第七次大流行菌株中被发现，并参与有效的肠道定植和趋化性调节。降解3'3'-cGAMP的磷酸二酯酶（PDEs）在相关信号通路中起重要的调节作用，先前的一项研究在霍乱弧菌中鉴定出了三种PDEs，即V - cGAP1、V - cGAP2和V - cGAP3，它们在3'3'-cGAMP降解中起作用。我们报道了V - cGAP3的晶体结构、生化及结构分析，为理解3'3'-cGAMP降解和一般调节机制提供了基础。我们的晶体结构和分子动力学（MD）模拟结构显示，V - cGAP3在其N端和C端结构域内包含串联的HD - GYP结构域，尽管它们的序列同源性较低，但具有相似的三维拓扑结构。生化和结构分析表明，N端结构域对具有催化作用的C端结构域起正调节机制。我们还证明了其他同源的弧菌PDEs，即V - cGAP1/2，可能通过类似的机制发挥作用。（C）2018年由爱思唯尔有限公司出版