Transmembrane Domain 3 (TM3) Governs Orai1 and Orai3 Pore Opening in an Isoform-Specific Manner
| Autor: | Carmen Höglinger, Marc Fahrner, Adéla Tiffner, Matthias Sallinger, Sarah Weiß, Isabella Derler, Lena Maltan, Herwig Grabmayr |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Gene isoform Orai1 Orai3 STIM1 Mutant Gating 03 medical and health sciences Cell and Developmental Biology 0302 clinical medicine isoform-specific activation lcsh:QH301-705.5 Original Research chemistry.chemical_classification Chemistry ORAI1 Cell Biology CRAC channel Amino acid Transmembrane domain Cytosol 030104 developmental biology lcsh:Biology (General) Biophysics 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | Frontiers in Cell and Developmental Biology Frontiers in Cell and Developmental Biology, Vol 9 (2021) |
| ISSN: | 2296-634X |
| Popis: | 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. Graphical Abstract Orai1 and Orai3 channel activation depends in an isoform-specific manner on two non-conserved residues in TM3 (Orai1: V181, L185, Orai3: A156, F160). Mutation of these residues to alanine leads in the absence of STIM1 to small constitutive activity of the respective Orai1 mutants, however, to huge constitutive currents of the respective Orai3 mutants. Overall, two non-conserved residues in TM3 control the maintenance of the closed state as well as an opening permissive conformation of Orai channels in an isoform-specific manner. |
| Databáze: | OpenAIRE |
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