eATP sensing by the purinergic receptor PA2072 for allosteric modulation in intracellular c-di-GMP signaling

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 <i><i>Pseudomonas aeruginosa</i></i> 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.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-11-04
DOI
https://doi.org/10.1073/pnas.2423664122
Primary Topic
Adenosine and Purinergic Signaling
Type
article
Field-Weighted Citation Impact
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article

eATP sensing by the purinergic receptor PA2072 for allosteric modulation in intracellular c-di-GMP signaling

Xinghua Jin, Yangyang Xu, Haitao Yang, Jiaqing Zhao et al.
Proceedings of the National Academy of Sciences
Adenosine and Purinergic Signaling
article

eATP sensing by the purinergic receptor PA2072 for allosteric modulation in intracellular c-di-GMP signaling

Xinghua Jin, Yangyang Xu, Haitao Yang, Jiaqing Zhao, Shuo Shi, Wangxin Xiao, Xun‐Cheng Su, Zhi Lin, Yunjie Xiao, Huimin Zhang, Guowei Yin, Yan Zhang, Xiaojing Gao, Cheng Chen, Tingting Yang, Zefang Wang, Weidong Huang, Wensu Yuan, Yajing Duan
article en

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 <i><i>Pseudomonas aeruginosa</i></i> 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.

Proceedings of the National Academy of SciencesVol. 122(45)
Sun Yat-sen University (CN), Tianjin University (CN), Nankai University (CN), ShanghaiTech University (CN), Tianjin Synthetic Material Research Institute (China) (CN), The Seventh Affiliated Hospital of Sun Yat-sen University (CN), Ningxia Medical University (CN), State Key Laboratory of Synthetic Chemistry (CN), Ningxia Center for Diseases Prevention and Control (CN)
Openalex Percentile: Top 67%
Adenosine and Purinergic Signaling
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