title: STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1.
abstract: Store-operated Ca(2+) channels activated by the depletion of Ca(2+) from the endoplasmic reticulum (ER) are a major Ca(2+) entry pathway in nonexcitable cells and are essential for T cell activation and adaptive immunity. After store depletion, the ER Ca(2+) sensor STIM1 and the CRAC channel protein Orai1 redistribute to ER-plasma membrane (PM) junctions, but the fundamental issue of how STIM1 activates the CRAC channel at these sites is unresolved. Here, we identify a minimal, highly conserved 107-aa CRAC activation domain (CAD) of STIM1 that binds directly to the N and C termini of Orai1 to open the CRAC channel. Purified CAD forms a tetramer that clusters CRAC channels, but analysis of STIM1 mutants reveals that channel clustering is not sufficient for channel activation. These studies establish a molecular mechanism for store-operated Ca(2+) entry in which the direct binding of STIM1 to Orai1 drives the accumulation and the activation of CRAC channels at ER-PM junctions.
authors.affiliation: Department of Neurobiology, Stanford University School of Medicine, CA 94305, USA.
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Park
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hoover
authors.forename: Franklin M
authors.initials: FM
authors.lastname: Mullins
authors.forename: Priti
authors.initials: P
authors.lastname: Bachhawat
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Covington
authors.forename: Stefan
authors.initials: S
authors.lastname: Raunser
authors.forename: Thomas
authors.initials: T
authors.lastname: Walz
authors.forename: K Christopher
authors.initials: KC
authors.lastname: Garcia
authors.forename: Ricardo E
authors.initials: RE
authors.lastname: Dolmetsch
authors.forename: Richard S
authors.initials: RS
authors.lastname: Lewis
mesh_terms: D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism*; D020013:Calcium Signaling; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D000071740:ORAI1 Protein; D017434:Protein Structure, Tertiary; D000071737:Stromal Interaction Molecule 1
chemical_list: D015220:Calcium Channels; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1