Activation of STIM1‐Orai1 involves an intramolecular switching mechanism

Abstract

The cytosolic level of Ca2+ has to be under tight control since Ca2+ is a potent regulator of many pivotal cellular functions. Store operated calcium entry (SOCE) is a major calcium entry mechanism present in virtually all cell types. Its activity is controlled by the luminal Ca2+ concentration of the ER. The stromal interaction molecule (STIM1) located in the ER, which is the Ca2+ sensor, and the highly Ca2+ selective Orai1 channels in the plasma membrane are the two main component of this machinery. Decreased ER luminal Ca2+ concentrations trigger oligomerization and clustering of STIM1, which, in turn, becomes capable of activating Orai1 channels. The Orai1 activating region within the STIM1 cytoplasmic part has been recently identified (CAD/SOAR) Here, we identified an acidic motif in STIM1 that keeps CAD/SOAR domain in an inactive state. Intriguingly, the sequence of the STIM1 acidic motif shows substantial similarity to that of the C‐terminal coiled‐coil segment of Orai1, which is the postulated site of interaction with STIM1. Mutations within this acidic region make STIM1 constitutively active presumably by preventing the intramolecular interaction with a short basic segment within the CAD/SOAR domain that is also essential for Orai1 activation. We propose that the CAD/SOAR domain is released from an intramolecular clamp during STIM1 activation, allowing activation of Orai1 channels.