Sequential Steps of CRAC Channel Activation.
Interaction between the endoplasmic reticulum protein STIM1 and the plasma membrane channel ORAI1 generates calcium signals that are central for diverse cellular functions. How STIM1 binds and activates ORAI1 remains poorly understood. Using electrophysiological, optical, and biochemical techniques, we examined the effects of mutations in the STIM1-ORAI1 activating region (SOAR) of STIM1. We find that SOAR mutants that are deficient in binding to resting ORAI1 channels are able to bind to and boost activation of partially activated ORAI1 channels. We further show that the STIM1 binding regions on ORAI1 undergo structural rearrangement during channel activation. The results suggest that activation of ORAI1 by SOAR occurs in multiple steps. In the first step, SOAR binds to ORAI1, partially activates the channel, and induces a rearrangement in the SOAR-binding site of ORAI1. That rearrangement of ORAI1 then permits sequential steps of SOAR binding, via distinct molecular interactions, to fully activate the channel.
['Palty|Raz|R|', 'Fu|Zhu|Z|', 'Isacoff|Ehud Y|EY|']
D001665:Binding Sites D002118:Calcium D015220:Calcium Channels D003600:Cytosol D057809:HEK293 Cells D006801:Humans D015640:Ion Channel Gating D008024:Ligands D050505:Mutant Proteins D009154:Mutation D000071740:ORAI1 Protein D011485:Protein Binding D011487:Protein Conformation D000071737:Stromal Interaction Molecule 1
CRAC channel STIM1 ORAI1 calcium gating