The STIM1: Orai interaction

Abstract

Ca2+ influx via store-operated Ca2+ release activated Ca2+ (CRAC) channels represents a main signalling pathway for a variety of cell functions, including T-cell activation as well as mast-cell degranulation. Depletion of [Ca2+]ER results in activation of Ca2+ channels within the plasmamembrane that mediate sustained Ca2+ influx which is required for refilling Ca2+ stores and down-stream Ca2+ signalling. The CRAC channel is the best characterized store-operated channel (SOC) with well-defined electrophysiological properties. In recent years, the molecular components of the CRAC channel have been defined. The ER – located Ca2+ -sensor, STIM1 and the Ca2+ -selective ion pore, Orai1 in the membrane are sufficient to fully reconstitute CRAC currents. Stromal interaction molecule (STIM) 1 is localized in the ER, senses [Ca2+]ER and activates the CRAC channel upon store depletion by direct binding to Orai1 in the plasmamembrane. The identification of STIM1 and Orai1 and recently the structural resolution of both proteins by X-ray crystallography and nuclear magnetic resonance substantiated many findings from structure-function studies which has substantially improved the understanding of CRAC channel activation. Within this review, we summarize the functional and structural mechanisms of CRAC channel regulation, present a detailed overview of the STIM1/Orai1 signalling pathway where we focus on the critical domains mediating interactions and on the ion permeation pathway. We portray a mechanistic view of the steps in the dynamics of CRAC channel signalling ranging from STIM1 oligomerization over STIM1-Orai1 coupling to CRAC channel activation and permeation.