Sequential Steps of CRAC Channel Activation

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Raz Palty, Zhu Fu, Ehud Y. Isacoff
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.

Graphical abstract

Teaser

How the interaction between STIM1 and the ORAI1 CRAC channel activates ORAI1 is poorly understood. Palty et al. identify mutations in STIM1 that disrupt partial activation but support the transition from partial to full activation. The study reveals the existence of sequential modes of STIM1-ORAI1 interaction.


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