Sterol hindrance of Orai activation

Abstract

Orai channels at the plasma membrane mediate store-operated Ca(2+) entry in response to Ca(2+) depletion of the endoplasmic reticulum. Orai channels are gated by stromal-interacting molecule proteins, which act as Ca(2+) sensors, and the association of these proteins is enhanced in cholesterol-rich lipid rafts. In research published in Science Signaling, Derler et al. report that cholesterol inhibits Orai function through direct association with the channel amino terminus.

Fig. 1. Hypothetical model for cholesterol-Orai interactions

To illustrate the putative cholesterol-binding site, the Drosophila Orai structure [Protein Data Bank (PDB) accession number 4HKR] (7) was modified to match the sequence of human Orai1 by replacing Gln¹⁵² with Tyr. (A) (left) Human Orai1 is depicted in association with the STIM-Orai activating region (SOAR; PDB accession number 3TEQ) (11). (right) The N-terminal end of TM1 in human Orai1 was replaced with a 3₁₀ helix, a conformation that might favor association with cholesterol at the expense of SOAR. (B) Detailed view of hypothetical SOAR-Orai1 interaction in cholesterol-free Orai1. (C) Detailed view of hypothetical cholesterol-Orai1 interaction. (D) End-on view of Orai1-TM1 as an α-helix, to illustrate the orientation of Leu⁷⁴ and Tyr⁸⁰ side chains in this conformation. (E) End-on view of Orai1-TM1 as a 3₁₀ helix to illustrate the orientation of the key cholesterol-binding residues in this conformation.