2. Academic Validation
  3. Photocrosslinking-induced CRAC channel-like Orai1 activation independent of STIM1

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

  • Nat Commun. 2023 Mar 8;14(1):1286. doi: 10.1038/s41467-023-36458-4.
Lena Maltan # 1,  Sarah Weiß # 1,  Hadil Najjar # 1,  Melanie Leopold 1,  Sonja Lindinger 1,  Carmen Höglinger 1,  Lorenz Höbarth 1,  Matthias Sallinger 1,  Herwig Grabmayr 1,  Sascha Berlansky 1,  Denis Krivic 2,  Valentina Hopl 1,  Anna Blaimschein 1,  Marc Fahrner 1,  Irene Frischauf 1,  Adéla Tiffner 1,  Isabella Derler 3
Affiliations

Affiliations

  • 1 Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz, A-4020, Linz, Austria.
  • 2 Division of Medical Physics and Biophysics, Gottfried Schatz Research Center, Medical University of Graz, A-8010, Graz, Austria.
  • 3 Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz, A-4020, Linz, Austria. Isabella.derler@jku.at.
  • # Contributed equally.
PMID: 36890174 DOI: 10.1038/s41467-023-36458-4
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.

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