Molecular Mechanisms of STIM1-Mediated Orai-1 Channel Activation

Abstract

Immune response mechanisms at a cellular level are mostly triggered by a decrease in the concentration of Ca2+ within the endoplasmic reticulum (ER), followed by the opening of the calcium release-activated calcium (CRAC) channels that leads to increased intracellular Ca2+ concentrations. Recently, the stromal interaction molecule (STIM) was determined to be the ER Ca2+ sensor that activates the channel in response to the depletion of intracellular calcium content. However, the molecular details of STIM interaction with Orai that causes the channel opening are not yet known. Understanding these molecular processes would shed light on this signal transduction pathway and opens up new doors for tapping into such a mechanism with profound biological and clinical implications.CRAC channels in the plasma membrane are integral membrane proteins that play a central role in cellular signaling by generating the calcium influx. Orai protein is a pore subunit of the channel, which has 3 homologs (Orai-1, Orai-2, and Orai-3).We develop all-atomic molecular dynamics models of the STIM1/Orai-1 complex with the aim to demonstrate how the binding of STIM1 to C-terminus of Orai-1 will result in a conformational change in Orai-1 protein complex leading to the activation of CRAC channels. Different mutations of Orai-1 C-terminus are considered and the influence of factors such as ER tension on the enhancement of this conformational change is explored in accordance with experimental evidences.