Structural Insights into Divalent Cation Modulations of ATP-Gated P2X Receptor Channels
Go Kasuya,
Yuichiro Fujiwara,
Mizuki Takemoto,
Naoshi Dohmae,
Yoshiko Nakada-Nakura,
Ryuichiro Ishitani,
Motoyuki Hattori,
Osamu Nureki
Affiliations
Go Kasuya
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
Yuichiro Fujiwara
Department of Physiology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
Mizuki Takemoto
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
Naoshi Dohmae
Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
Yoshiko Nakada-Nakura
Department of Cell Biology, Graduate School of Medicine, Kyoto University, Konoe-cho, Yoshida Sakyo-ku, Kyoto 606-8501, Japan
Ryuichiro Ishitani
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
Motoyuki Hattori
State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, Department of Physiology and Biophysics, School of Life Sciences, Fudan University, 2005 Songhu Road, Yangpu District, Shanghai 200438, China
Osamu Nureki
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
P2X receptors are trimeric ATP-gated cation channels involved in physiological processes ranging widely from neurotransmission to pain and taste signal transduction. The modulation of the channel gating, including that by divalent cations, contributes to these diverse physiological functions of P2X receptors. Here, we report the crystal structure of an invertebrate P2X receptor from the Gulf Coast tick Amblyomma maculatum in the presence of ATP and Zn2+ ion, together with electrophysiological and computational analyses. The structure revealed two distinct metal binding sites, M1 and M2, in the extracellular region. The M1 site, located at the trimer interface, is responsible for Zn2+ potentiation by facilitating the structural change of the extracellular domain for pore opening. In contrast, the M2 site, coupled with the ATP binding site, might contribute to regulation by Mg2+. Overall, our work provides structural insights into the divalent cation modulations of P2X receptors.
