Photocrosslinking-induced CRAC channel-like Orai1 activation independent of STIM1

Lena Maltan, Sarah Weiß, Hadil Najjar, Melanie Leopold, Sonja Lindinger, Carmen Höglinger, Lorenz Höbarth, Matthias Sallinger, Herwig Grabmayr, Sascha Berlansky, Denis Krivic, Valentina Hopl, Anna Blaimschein, Marc Fahrner, Irene Frischauf, Adéla Tiffner and Isabella Derler ()
Additional contact information
Lena Maltan: Johannes Kepler University Linz
Sarah Weiß: Johannes Kepler University Linz
Hadil Najjar: Johannes Kepler University Linz
Melanie Leopold: Johannes Kepler University Linz
Sonja Lindinger: Johannes Kepler University Linz
Carmen Höglinger: Johannes Kepler University Linz
Lorenz Höbarth: Johannes Kepler University Linz
Matthias Sallinger: Johannes Kepler University Linz
Herwig Grabmayr: Johannes Kepler University Linz
Sascha Berlansky: Johannes Kepler University Linz
Denis Krivic: Medical University of Graz
Valentina Hopl: Johannes Kepler University Linz
Anna Blaimschein: Johannes Kepler University Linz
Marc Fahrner: Johannes Kepler University Linz
Irene Frischauf: Johannes Kepler University Linz
Adéla Tiffner: Johannes Kepler University Linz
Isabella Derler: Johannes Kepler University Linz

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Ca2+ release-activated Ca2+ (CRAC) channels, indispensable for the immune system and various other human body functions, consist of two transmembrane (TM) proteins, the Ca2+-sensor STIM1 in the ER membrane and the Ca2+ ion channel Orai1 in the plasma membrane. Here we employ genetic code expansion in mammalian cell lines to incorporate the photocrosslinking unnatural amino acids (UAA), p-benzoyl-L-phenylalanine (Bpa) and p-azido-L-phenylalanine (Azi), into the Orai1 TM domains at different sites. Characterization of the respective UAA-containing Orai1 mutants using Ca2+ imaging and electrophysiology reveal that exposure to UV light triggers a range of effects depending on the UAA and its site of incorporation. In particular, photoactivation at A137 using Bpa in Orai1 activates Ca2+ currents that best match the biophysical properties of CRAC channels and are capable of triggering downstream signaling pathways such as nuclear factor of activated T-cells (NFAT) translocation into the nucleus without the need for the physiological activator STIM1.

Date: 2023
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DOI: 10.1038/s41467-023-36458-4

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