Store-operated calcium entry mediated by stromal interaction molecule 1 (STIM1) and ORAI1 constitutes one of the major calcium entry routes in mammalian cells. STIM1 protein, a calcium sensor in the endoplasmic reticulum (ER), transduces calcium signals from ER to the cytoplasm and interact physically with ORAI1, a calcium channel located in the plasma membrane. Although considerable understandings into the STIM–ORAI pathway have been obtained from cellular studies, the mechanistic underpinnings of this inside-out calcium signaling, particularly the crucial questions of how ER-luminal signals are transmitted towards the STIM1 cytoplasmic domain (STIM1-CT) and how the STIM1 juxtamembrane coiled-coil region (CC1) interplays with the ORAI-activating domain (CAD/SOAR) have not been addressed.

Recently, three research groups led by Dr. WANG Junfeng (High Magnetic Field Laboratory, Chinese Academy of Sciences), Dr. ZHOU Yubin (Texas A&M University) and Dr. WANG Youjun (Beijing Normal University) have made great progress in the study of STIM1 protein.

The researchers adopted a ‘divide-to-conquer’ strategy to tackle this inside-out signaling problem. They discovered that a mutant C227W represents STIM1 in one of its activated states, which enables them to probe the conformational changes within the transmembrane domain both in vitro and in vivo. Local rearrangement, rather than alterations in the oligomeric state of STIM1-TM, is sufficient to prompt conformational changes in the juxtamembrane CC1 region. Importantly, the researchers further identified critical residues within the cytoplasmic domain of STIM1 (STIM1-CT) that entail autoinhibition. On the basis of these findings, they propose a model in which STIM1-TM reorganization switches STIM1-CT into an extended conformation, thereby projecting the ORAI-activating domain to gate ORAI1 channels.

This work was supported by the National Basic Research Program of China (973 Program, No.2012CB917202).

The work entitled “Inside-out Ca2+ signalling prompted by STIM1 conformational switch” was published in Nature Communications.