Transmembrane Domain 3 (TM3) Governs Orai1 and Orai3 Pore Opening in an Isoform-Specific Manner.
CRAC channel
Orai1
Orai3
STIM1
isoform-specific activation
Journal
Frontiers in cell and developmental biology
ISSN: 2296-634X
Titre abrégé: Front Cell Dev Biol
Pays: Switzerland
ID NLM: 101630250
Informations de publication
Date de publication:
2021
2021
Historique:
received:
30
11
2020
accepted:
21
01
2021
entrez:
1
3
2021
pubmed:
2
3
2021
medline:
2
3
2021
Statut:
epublish
Résumé
STIM1-mediated activation of calcium selective Orai channels is fundamental for life. The three Orai channel isoforms, Orai1-3, together with their multiple ways of interplay, ensure their highly versatile role in a variety of cellular functions and tissues in both, health and disease. While all three isoforms are activated in a store-operated manner by STIM1, they differ in diverse biophysical and structural properties. In the present study, we provide profound evidence that non-conserved residues in TM3 control together with the cytosolic loop2 region the maintenance of the closed state and the configuration of an opening-permissive channel conformation of Orai1 and Orai3 in an isoform-specific manner. Indeed, analogous amino acid substitutions of these non-conserved residues led to distinct extents of gain- (GoF) or loss-of-function (LoF). Moreover, we showed that enhanced overall hydrophobicity along TM3 correlates with an increase in GoF mutant currents. Conclusively, while the overall activation mechanisms of Orai channels appear comparable, there are considerable variations in gating checkpoints crucial for pore opening. The elucidation of regions responsible for isoform-specific functional differences provides valuable targets for drug development selective for one of the three Orai homologs.
Identifiants
pubmed: 33644073
doi: 10.3389/fcell.2021.635705
pmc: PMC7905104
doi:
Types de publication
Journal Article
Langues
eng
Pagination
635705Subventions
Organisme : Austrian Science Fund FWF
ID : P 30567
Pays : Austria
Organisme : Austrian Science Fund FWF
ID : W 1250
Pays : Austria
Informations de copyright
Copyright © 2021 Tiffner, Maltan, Fahrner, Sallinger, Weiß, Grabmayr, Höglinger and Derler.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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