Relative motions between left flipper and dorsal fin domains favour P2X4 receptor activation

Wen-Shan Zhao, Jin Wang, Xiao-Juan Ma, Yang Yang, Yan Liu, Li-Dong Huang, Ying-Zhe Fan, Xiao-Yang Cheng, Hong-Zhuan Chen, Rui Wang () and Ye Yu ()
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Wen-Shan Zhao: Shanghai Jiao Tong University School of Medicine
Jin Wang: Shanghai Jiao Tong University School of Medicine
Xiao-Juan Ma: Shanghai Jiao Tong University School of Medicine
Yang Yang: Shanghai Jiao Tong University School of Medicine
Yan Liu: Shanghai Jiao Tong University School of Medicine
Li-Dong Huang: Shanghai Jiao Tong University School of Medicine
Ying-Zhe Fan: Putuo District Center Hospital, Shanghai University of Chinese Traditional Medicine
Xiao-Yang Cheng: Shanghai Jiao Tong University School of Medicine
Hong-Zhuan Chen: Shanghai Jiao Tong University School of Medicine
Rui Wang: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University
Ye Yu: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: Abstract Channel gating in response to extracellular ATP is a fundamental process for the physiological functions of P2X receptors. Here we identify coordinated allosteric changes in the left flipper (LF) and dorsal fin (DF) domains that couple ATP-binding to channel gating. Engineered disulphide crosslinking or zinc bridges between the LF and DF domains that constrain their relative motions significantly influence channel gating of P2X4 receptors, confirming the essential role of these allosteric changes. ATP-binding-induced alterations in interdomain hydrophobic interactions among I208, L217, V291 and the aliphatic chain of K193 correlate well with these coordinated relative movements. Mutations on those four residues lead to impaired or fully abolished channel activations of P2X4 receptors. Our data reveal that ATP-binding-induced altered interdomain hydrophobic interactions and the concomitant coordinated motions of LF and DF domains are allosteric events essential for the channel gating of P2X4 receptors.

Date: 2014
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DOI: 10.1038/ncomms5189

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