The human Orai1 (hOrai1) channel plays a crucial role in extracellular Ca influx and has emerged as an attractive drug target for various diseases. However, the activated structure of the hOrai1 channel assembly within a lipid bilayer remains unknown. In this study, we expressed and purified the hOrai1 channel covalently linked to two SOAR tandems (HOSS). Patch-clamp experiments in whole-cell configuration showed that HOSS is constitutively active. Biochemical characterization confirmed that the purified HOSS channels were successfully incorporated into MSP1E3D1 nanodiscs. Negative staining revealed that the HOSS channels resemble a mushroom, with the body representing the hOrai1 channel and the leg representing the SOAR domain. Surprisingly, 2D analysis of cryo-EM data demonstrated a pentameric assembly of HOSS in a lipid bilayer. Our findings suggest that the hOrai1 channel may assemble into different oligomeric states in response to varying membrane environments.
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