Discovery of novel gating checkpoints in the Orai1 calcium channel by systematic analysis of constitutively active mutants of its paralogs and orthologs.

Augustynek, Bartlomiej; Gyimesi, Gergely; Dernič, Jan; Sallinger, Matthias; Albano, Giuseppe; Klesse, Gabriel J; Kandasamy, Palanivel; Grabmayr, Herwig; Frischauf, Irene; Fuster, Daniel G; Peinelt, Christine; Hediger, Matthias A; Bhardwaj, Rajesh (2022). Discovery of novel gating checkpoints in the Orai1 calcium channel by systematic analysis of constitutively active mutants of its paralogs and orthologs. Cell calcium, 105, p. 102616. Elsevier 10.1016/j.ceca.2022.102616

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In humans, there are three paralogs of the Orai Ca2+ channel that form the core of the store-operated calcium entry (SOCE) machinery. While the STIM-mediated gating mechanism of Orai channels is still under active investigation, several artificial and natural variants are known to cause constitutive activity of the human Orai1 channel. Surprisingly, little is known about the conservation of the gating checkpoints among the different human Orai paralogs and orthologs in other species. In our work, we show that the mutation corresponding to the activating mutation H134A in transmembrane helix 2 (TM2) of human Orai1 also activates Orai2 and Orai3, likely via a similar mechanism. However, this cross-paralog conservation does not apply to the "ANSGA" nexus mutations in TM4 of human Orai1, which is reported to mimic the STIM1-activated state of the channel. In investigating the mechanistic background of these differences, we identified two positions, H171 and F246 in human Orai1, that are not conserved among paralogs and that seem to be crucial for the channel activation triggered by the "ANSGA" mutations in Orai1. However, mutations of the same residues still allow gating of Orai1 by STIM1, suggesting that the ANSGA mutant of Orai1 may not be a surrogate for the STIM1-activated state of the Orai1 channel. Our results shed new light on these important gating checkpoints and show that the gating mechanism of Orai channels is affected by multiple factors that are not necessarily conserved among orai homologs, such as the TM4-TM3 coupling.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Nephrologie / Hypertonie
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)

UniBE Contributor:

Augustynek, Bartlomiej Stanislaw, Gyimesi, Gergely (A), Dernič, Jan, Albano, Giuseppe, Klesse, Gabriel Jonathan, Kandasamy, Palanivel, Fuster, Daniel Guido, Peinelt, Christine, Hediger, Matthias, Bhardwaj, Rajesh

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

0143-4160

Publisher:

Elsevier

Language:

English

Submitter:

Pubmed Import

Date Deposited:

07 Jul 2022 10:44

Last Modified:

29 Mar 2023 23:38

Publisher DOI:

10.1016/j.ceca.2022.102616

PubMed ID:

35792401

Uncontrolled Keywords:

ANSGA Calcium Orai1 Orai2 Orai3 STIM1

BORIS DOI:

10.48350/171152

URI:

https://boris.unibe.ch/id/eprint/171152

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