Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 292, Issue 18, Pages 7619-7635Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.771121
Keywords
conformational change; gating; ion channel; protein domain; receptor structure-function; P2X receptors; molecular simulations; physical couplings; single channel recording
Categories
Funding
- National Natural Science Foundation of China [31570832, 31170787, 31400707]
- National Program on Key Basic Research Project of China [2014CB910302]
- National Excellent Young Scientist Foundation of China [31222018]
- Science and Technology Fund of Shanghai Jiao Tong University School of Medicine Grant [13XJ10042]
- Opening Project of State Key Laboratory of Drug Research Grant [SIMM1601KF-02]
- Doctoral Innovation Fund Projects from Shanghai Jiao Tong University School of Medicine Grant [BXJ201405]
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P2X receptors are ATP-gated trimeric channels with important roles in diverse pathophysiological functions. A detailed understanding of the mechanism underlying the gating process of these receptors is thus fundamentally important and may open new therapeutic avenues. The left flipper (LF) domain of the P2X receptors is a flexible loop structure, and its coordinated motions together with the dorsal fin (DF) domain are crucial for the channel gating of the P2X receptors. However, the mechanism underlying the crucial role of the LF domain in the channel gating remains obscure. Here, we propose that the ATP-induced allosteric changes of the LF domain enable it to foster intersubunit physical couplings among the DF and two lower body domains, which are pivotal for the channel gating of P2X4 receptors. Metadynamics analysis indicated that these newly established intersubunit couplings correlate well with the ATP-bound open state of the receptors. Moreover, weakening or strengthening these physical interactions with engineered intersubunit metal bridges remarkably decreased or increased the open probability of the receptors, respectively. Further disulfide cross-linking and covalent modification confirmed that the intersubunit physical couplings among the DF and two lower body domains fostered by the LF domain at the open state act as an integrated structural element that is stringently required for the channel gating of P2X4 receptors. Our observations provide new mechanistic insights into P2X receptor activation and will stimulate development of new allosteric modulators of P2X receptors.
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