Abstract
Store-operated calcium entry (SOCE) is a mechanism of calcium influx activated after the depletion of intracellular stores. The main components of this mechanism are Orai1, the calcium channel, and STIM1 a calcium sensor, which oligomerizes and activates Orai channels when calcium levels drop inside the endoplasmic reticulum. The activation of Orai1 requires a series of molecular rearrangements of STIM1, which culminate in the final exposition of a domain within STIM1 known as SOAR (Stim Orai Activating Region). Specialized plasma membrane regions enriched in sphingolipids and cholesterol, have been shown to modulate SOCE also. In this work, we identified in the SOAR region a cholesterol recognition/interaction amino acid consensus (CRAC) domain, which appears to be important for the STIM1-Orai1 interaction. Through mutagenesis of this domain, we found by FRET microscopy that SOAR and STIM1 mutated in the CRAC domain loose its capacity to interact with Orai1. This finding suggests that the association of STIM1 to cholesterol resides in a discrete region in STIM1 and may play an important role for the subsequent STIM1-Orai1 association.
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