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STIM1 couples to ORAI1 via an intramolecular transition into an extended conformation
Author(s) -
Muik Martin,
Fahrner Marc,
Schindl Rainer,
Stathopulos Peter,
Frischauf Irene,
Derler Isabella,
Plenk Peter,
Lackner Barbara,
Groschner Klaus,
Ikura Mitsuhiko,
Romanin Christoph
Publication year - 2011
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2011.79
Subject(s) - biology , transition (genetics) , intramolecular force , orai1 , biophysics , stim1 , evolutionary biology , computational biology , microbiology and biotechnology , genetics , stereochemistry , endoplasmic reticulum , chemistry , gene
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.