The STIM1/Orai signaling machinery

Abstract

Ca2+ influx via store-operated Ca2+ release activated Ca2+ (CRAC) channels represents a main signaling pathway for T cell activation as well as mast-cell degranulation. The ER located Ca2+ sensor, STIM1 and the Ca2+ selective ion pore, Orai1 in the membrane are sufficient to fully reconstitute CRAC currents. Their identification, but even more the recent structural resolu¬tion of both proteins by X ray crystallography has substantially advanced the understanding of the activation mechanism of CRAC channels. In this review, we provide a detailed descrip¬tion of the STIM1/Orai1 signaling pathway thereby focusing on the critical domains mediating both, intra as well as intermo¬lecular interactions and on the ion permeation pathway. Based on the results of functional studies as well as the recently pub¬lished crystal structures, we portray a mechanistic view of the steps in the CRAC channel signaling cascade ranging from STIM1 oligomerization over STIM1 Orai1 coupling to the ulti-mate Orai1 channel activation and permeation.