Initial activation of STIM1, the regulator of store-operated calcium entry

Abstract

Physiological Ca ²⁺ signalling in T lymphocytes and other cells depends on the STIM-ORAI pathway of store-operated Ca ²⁺ entry. STIM1 and STIM2 are Ca ²⁺ sensors located in the endoplasmic reticulum (ER) membrane, with ER-luminal domains that monitor cellular Ca ²⁺ stores and cytoplasmic domains that gate ORAI channels in the plasma membrane. The STIM ER-luminal domain dimerizes or oligomerizes upon dissociation of Ca ²⁺, but the mechanism transmitting activation to the STIM cytoplasmic domain has not been defined. Here we demonstrate, using Tb ³⁺–acceptor energy transfer, that dimerization of STIM1 ER-luminal domains can initiate an extensive conformational change in murine STIM1 cytoplasmic domains. The conformational change, triggered by apposition of the predicted coiled-coil 1 (CC1) regions, releases the ORAI-activating domains from their interaction with the CC1 regions and allows physical extension of the STIM1 cytoplasmic domain across the gap between ER and plasma membrane to communicate with ORAI channels.