STIM1-Induced Conformational Transition of ORAI-1 Leads to Channel Activation

Abstract

Calcium release-activated calcium (CRAC) channels in the plasma membrane are integral membrane proteins that play a central role in cellular signaling by generating the calcium influx. The calcium influx results in a decrease in the concentration of Ca2+ within the endoplasmic reticulum (ER) that triggers the immune system response. The stromal interaction molecule (STIM1) detects the decline of ER Ca2+ concentration and activates the channel. The molecular details of STIM1 interaction with Orai1 (a pore subunit of the channel) that causes the channel opening are not yet clear. In order to understand the molecular details of this signal transduction pathway, we developed all-atomic molecular models of the STIM1/Orai-1 complex and studied the binding of STIM1 to C-terminus of Orai-1 leading to conformational changes in Orai-1 protein complex followed by the activation of the CRAC channels. In this study, we examined the effect of different point mutations of the C-terminus of Orai-1 and ER tension on the STIM-induced conformational transition of Orai-1 that was further compared with previous experimental studies. Our results showed that the M1 helices of Orai1 are slightly bent in the region that spans the junction between the hydrophobic and basic portions of the pore. This raises the possibility that the conformation of the basic region could change, perhaps as part of the gating process, while the hydrophobic section and glutamate ring remain fairly fixed. Furthermore, we observed that the distance between M1 helices on the cytoplasmic site is increased resulting in the expected widening of the cytoplasmic region of the pore.