Molecular understanding of calcium permeation through the open Orai channel

Xiaofen Liu; Guangyan Wu; Yi Yu; Xiaozhe Chen; Renci Ji; Jing Lu; Xin Li; Xing Zhang; Xue Yang; Yuequan Shen

doi:10.1371/journal.pbio.3000096

Molecular understanding of calcium permeation through the open Orai channel

PLoS Biol. 2019 Apr 22;17(4):e3000096. doi: 10.1371/journal.pbio.3000096. eCollection 2019 Apr.

Authors

Xiaofen Liu¹, Guangyan Wu¹, Yi Yu¹, Xiaozhe Chen¹, Renci Ji¹, Jing Lu¹, Xin Li¹, Xing Zhang², Xue Yang¹, Yuequan Shen^{1

3}

Affiliations

¹ State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin, China.
² School of Medicine, Zhejiang University, Hangzhou, China.
³ Synergetic Innovation Center of Chemical Science and Engineering, Tianjin, China.

Abstract

The Orai channel is characterized by voltage independence, low conductance, and high Ca2+ selectivity and plays an important role in Ca2+ influx through the plasma membrane (PM). How the channel is activated and promotes Ca2+ permeation is not well understood. Here, we report the crystal structure and cryo-electron microscopy (cryo-EM) reconstruction of a Drosophila melanogaster Orai (dOrai) mutant (P288L) channel that is constitutively active according to electrophysiology. The open state of the Orai channel showed a hexameric assembly in which 6 transmembrane 1 (TM1) helices in the center form the ion-conducting pore, and 6 TM4 helices in the periphery form extended long helices. Orai channel activation requires conformational transduction from TM4 to TM1 and eventually causes the basic section of TM1 to twist outward. The wider pore on the cytosolic side aggregates anions to increase the potential gradient across the membrane and thus facilitate Ca2+ permeation. The open-state structure of the Orai channel offers insights into channel assembly, channel activation, and Ca2+ permeation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Calcium / metabolism*
Calcium / physiology
Calcium Channels / metabolism*
Cell Membrane / metabolism
Cryoelectron Microscopy
Drosophila Proteins / genetics
Drosophila Proteins / metabolism*
Drosophila melanogaster / metabolism
Ion Channel Gating / physiology
Membrane Proteins / metabolism
ORAI1 Protein / genetics
ORAI1 Protein / metabolism*
Protein Structure, Secondary

Substances

Calcium Channels
Drosophila Proteins
Membrane Proteins
ORAI1 Protein
olf186-F protein, Drosophila
Calcium

Grants and funding

This work was supported by National Key Research and Development Program of China (grant 2017YFA0504801 to YS; 2017YFA0504803 and 2018YFA0507700 to XZ), National Natural Science Foundation of China (grants 31570750 YS and 31870834 to YS; grant 31870736 to XY), Ph.D Candidate Research Innovation Fund of Nankai University and the Fundamental Research Funds for the Central Universities (2018XZZX001-13) to XZ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.