eATP sensing by the purinergic receptor PA2072 for allosteric modulation in intracellular c-di-GMP signaling
Abstract
Extracellular ATP (eATP) has emerged as a crucial signaling molecule across eukaryotic and prokaryotic domains, modulating diverse cellular functions by activating purinergic receptors to initiate intracellular signaling cascades. However, the structural and molecular mechanisms underlying eATP sensing and signaling by prokaryotic receptors remain largely unknown. Here, we demonstrate that the receptor PA2072 in Pseudomonas aeruginosa is responsible for recognizing eATP to down-regulate intracellular cyclic di-GMP levels. The periplasmic CHASE4 domain of PA2072 specifically binds and hydrolyzes eATP, exhibiting ATPase activity both in the presence and absence of a divalent cation cofactor. Structural elucidation of the PA2072 CHASE4 domain in its monomeric and complex states unveils an exquisite molecular switch governed by the oligomeric state. ATP hydrolysis by the catalytically active monomeric form is coupled to homodimerization, concomitantly deactivating its ATPase activity and initiating intracellular phosphodiesterase activity. These findings open avenues for understanding interkingdom eATP signaling and developing targeted therapeutic interventions.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (19)
Yan Zhang
Xiaojing Gao
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Ningxia Medical University
Yunjie Xiao
Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University
Yajing Duan
Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University
Wangxin Xiao
Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University
Yangyang Xu
Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University
Tingting Yang
The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
Huimin Zhang
Cheng Chen
Shuo Shi
Xun-Cheng Su
State Key Laboratory of Elemento-Organic Chemistry, Frontiers Science Center for New Organic Matter, College of Chemistry
Xinghua Jin
School of Pharmaceutical Science and Technology, Tianjin University
Jiaqing Zhao
Research Center for Medical Science and Technology, Ningxia Medical University
Haitao Yang
Guowei Yin
Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University
Wensu Yuan
Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University
Zefang Wang
Key Laboratory of Material Simulation Methods & Software of Ministry of Education, College of Physics
Weidong Huang
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Ningxia Medical University
Zhi Lin
Department of Chemistry and Chemical Biology