2020
DOI: 10.1101/2020.09.03.281964
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Cryo-EM structure of the calcium release-activated calcium channel Orai in an open conformation

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 Å resolution. Comparison with previous closed structures reveals that opening… Show more

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Cited by 2 publications
(3 citation statements)
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References 78 publications
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“…Following store depletion, structural remodeling of the STIM1 C-terminus allows it to bridge the distance between the ER and PM at junctions where the membranes are only 10–25 nm apart from each other [ 191 ]. There, STIM1 forms tight contacts with the Orai1 channel, which forms a hexameric complex [ 192 , 193 , 194 , 195 ] with each subunit composed of four TM domains, a cytosolic N- and C-terminus, and two extracellular and one intracellular loop [ 33 , 35 , 38 ]. The Ca 2+ ion pore is formed in the center by six TM1 domains, which is surrounded by TM2 and TM3 and at the complex periphery by TM4 [ 192 , 193 , 194 , 195 ].…”
Section: Crac Channel Working Mechanismsmentioning
confidence: 99%
See 1 more Smart Citation
“…Following store depletion, structural remodeling of the STIM1 C-terminus allows it to bridge the distance between the ER and PM at junctions where the membranes are only 10–25 nm apart from each other [ 191 ]. There, STIM1 forms tight contacts with the Orai1 channel, which forms a hexameric complex [ 192 , 193 , 194 , 195 ] with each subunit composed of four TM domains, a cytosolic N- and C-terminus, and two extracellular and one intracellular loop [ 33 , 35 , 38 ]. The Ca 2+ ion pore is formed in the center by six TM1 domains, which is surrounded by TM2 and TM3 and at the complex periphery by TM4 [ 192 , 193 , 194 , 195 ].…”
Section: Crac Channel Working Mechanismsmentioning
confidence: 99%
“…There, STIM1 forms tight contacts with the Orai1 channel, which forms a hexameric complex [ 192 , 193 , 194 , 195 ] with each subunit composed of four TM domains, a cytosolic N- and C-terminus, and two extracellular and one intracellular loop [ 33 , 35 , 38 ]. The Ca 2+ ion pore is formed in the center by six TM1 domains, which is surrounded by TM2 and TM3 and at the complex periphery by TM4 [ 192 , 193 , 194 , 195 ]. TM4 is connected via a bent region, the so-called nexus [ 196 ], to the C-terminus, with the latter functioning as the main coupling site for STIM1 [ 179 ].…”
Section: Crac Channel Working Mechanismsmentioning
confidence: 99%
“…A total of six Orai monomers are required to form a functional channel pore. The TM domains thereby assemble as concentric rings around the ion-conducting pore in the centre, whereby the innermost ring that actually defines the pore is established by the six TM1 domains (Cai et al, 2016;Hou et al, 2012Hou et al, , 2018Hou et al, , 2020Liu et al, 2019;Yen et al, 2016). The single TM domain protein STIM contains an EF-hand as part of its ER luminal N-terminus that forms the basis of its Ca 2+ sensing ability by allowing it to bind Ca 2+ in a concentration-dependent manner (Fahrner et al, 2020;Stathopulos & Ikura, 2010).…”
Section: Introductionmentioning
confidence: 99%