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bioRxiv · 10.1101/2020.09.03.281964

Cryo-EM structure of the calcium release-activated calcium channel Orai in an open conformation

Hou, X.·Outhwaite, I. R.·Pedi, L.·Long, S. B.
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Abstract

The calcium release-activated calcium channel Orai regulates Ca2+ entry into non-excitable cells and is required for proper immune function. The channel typically opens following the release of Ca2+ from the endoplasmic reticulum. Certain pathologic mutations render the channel constitutively open. Here, using one such mutation (H206A), we present a cryo-EM structure of Orai from Drosophila melanogaster in an open conformation at 3.3 [A] resolution. Comparison with previous closed structures reveals that opening occurs through the outward movements of M1 helices that dilate the central pore. Repositionings of a ring of phenylalanine residues (F171) expose previously shielded glycine residues (G170) to the channel pore, despite the absence of significant rotational movement of the associated pore-lining helices. This phenylalanine ring and two rings of flanking hydrophobic amino acids act as a hydrophobic gate to control ion permeation. Extracellular M1-M2 turrets, not evident from previous Orai structures, form an electronegative pore entrance. Single sentence summaryA structure of the Ca2+ channel Orai in an open conformation provides insight into the opening mechanism of the channel and its role in regulating selective Ca2+ entry into immune and other non-excitable cells.

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Hou, X., Outhwaite, I. R., Pedi, L., Long, S. B.. 2020-09-04. Cryo-EM structure of the calcium release-activated calcium channel Orai in an open conformation. https://doi.org/10.1101/2020.09.03.281964

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