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

• Published in: Nature communications 2014-06, Vol.5 (1), p.4189-4189, Article 4189
• Main Authors: Zhao, Wen-Shan, Wang, Jin, Ma, Xiao-Juan, Yang, Yang, Liu, Yan, Huang, Li-Dong, Fan, Ying-Zhe, Cheng, Xiao-Yang, Chen, Hong-Zhuan, Wang, Rui, Yu, Ye
• Format: Article
• Language: English
• Subjects: 631/45/269; 631/57/2272; 9/74; Adenosine Triphosphate - metabolism; Allosteric Regulation; Amino Acid Motifs; Animals; Humanities and Social Sciences; Hydrophobic and Hydrophilic Interactions; Models, Molecular; multidisciplinary; Protein Structure, Tertiary; Rats; Receptors, Purinergic P2X4 - chemistry; Receptors, Purinergic P2X4 - genetics; Receptors, Purinergic P2X4 - metabolism; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms5189

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. P2X receptors are ion channels that are controlled by the level of extracellular ATP. Here, Zhao et al. describe the coordinated allosteric changes in two protein domains that couple extracellular ATP-binding to channel gating and show that these changes are essential for the function of the proteins.