Referenced in: none

Automatically associated channels: Kir2.3

Title: STIM1 couples to ORAI1 via an intramolecular transition into an extended conformation.

Authors: Martin Muik, Marc Fahrner, Rainer Schindl, Peter Stathopulos, Irene Frischauf, Isabella Derler, Peter Plenk, Barbara Lackner, Klaus Groschner, Mitsuhiko Ikura, Christoph Romanin

Journal, date & volume: EMBO J., 2011 May 4 , 30, 1678-89

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/21427704

Abstract
Stromal interaction molecule (STIM1) and ORAI1 are key components of the Ca(2+) release-activated Ca(2+) (CRAC) current having an important role in T-cell activation and mast cell degranulation. CRAC channel activation occurs via physical interaction of ORAI1 with STIM1 when endoplasmic reticulum Ca(2+) stores are depleted. Here we show, utilizing a novel STIM1-derived Förster resonance energy transfer sensor, that the ORAI1 activating small fragment (OASF) undergoes a C-terminal, intramolecular transition into an extended conformation when activating ORAI1. The C-terminal rearrangement of STIM1 does not require a functional CRAC channel, suggesting interaction with ORAI1 as sufficient for this conformational switch. Extended conformations were also engineered by mutations within the first and third coiled-coil domains in the cytosolic portion of STIM1 revealing the involvement of hydrophobic residues in the intramolecular transition. Corresponding full-length STIM1 mutants exhibited enhanced interaction with ORAI1 inducing constitutive CRAC currents, even in the absence of store depletion. We suggest that these mutant STIM1 proteins imitate a physiological activated state, which mimics the intramolecular transition that occurs in native STIM1 upon store depletion.