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STIM1 Clusters and Activates CRAC Channels via Direct Binding of a Cytosolic Domain to Orai1

2009; Cell Press; Volume: 136; Issue: 5 Linguagem: Inglês

10.1016/j.cell.2009.02.014

1097-4172

Chan Young Park, Paul Hoover, Franklin M. Mullins, Priti Bachhawat, Elizabeth D. Covington, Stefan Raunser, Thomas Walz, K. Christopher García, Ricardo E. Dolmetsch, Richard S. Lewis,

Neurobiology and Insect Physiology Research

Store-operated Ca2+ channels activated by the depletion of Ca2+ from the endoplasmic reticulum (ER) are a major Ca2+ entry pathway in nonexcitable cells and are essential for T cell activation and adaptive immunity. After store depletion, the ER Ca2+ 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 Ca2+ entry in which the direct binding of STIM1 to Orai1 drives the accumulation and the activation of CRAC channels at ER-PM junctions.