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Communication between N terminus and loop2 tunes Orai activation.

Marc Fahrner1, Saurabh K Pandey2, Martin Muik1

  • 1From the Institute of Biophysics, Johannes Kepler University of Linz, Gruberstrasse 40, 4020 Linz, Austria, and.

The Journal of Biological Chemistry
|December 15, 2017
PubMed
Summary

Calcium release-activated calcium (CRAC) channels are crucial for cellular calcium entry. This study reveals that the loop2 region, not the N-terminus, dictates isoform-specific Orai channel gating by modulating interactions.

Keywords:
atomic force microscopy (AFM)calcium release-activated calcium channel protein 1 (ORAI1)electrophysiologysignal transductionstromal interaction molecule 1 (STIM1)

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Area of Science:

  • Molecular Biology
  • Cell Physiology
  • Biophysics

Background:

  • Calcium release-activated calcium (CRAC) channels are essential for cellular calcium homeostasis.
  • These channels are formed by the interaction of STIM1 proteins and Orai channels.
  • Both Orai N-terminus and C-terminus are critical for Orai channel function and STIM1 interaction.

Purpose of the Study:

  • To investigate the structural basis for isoform-specific differences in Orai channel activation, particularly concerning N-terminal truncations.
  • To elucidate the role of the Orai N-terminus and loop2 regions in Orai channel gating and STIM1-mediated activation.

Main Methods:

  • Analysis of Orai1 and Orai3 mutants and chimeras.
  • Atomic force microscopy (AFM) to study protein structure.
  • Molecular dynamics (MD) simulations to model interactions.
  • Cysteine cross-linking to probe N-terminus and loop2 proximity.

Main Results:

  • Orai3 tolerates larger N-terminal truncations than Orai1 while maintaining function.
  • Distinct properties of Orai1 and Orai3 loop2 regions explain isoform-specific behaviors of N-truncation mutants.
  • Inhibitory interactions between the N-terminus and loop2 were observed in Orai1 mutants, but not Orai3.
  • Loop2 swapping between isoforms restored activation in N-truncated Orai1 mutants.
  • Mimicking N-terminus and loop2 proximity in full-length Orai1 inhibited STIM1-mediated currents.

Conclusions:

  • The loop2 region, not the N-terminus itself, is key to the differential regulation of Orai1 and Orai3 channel gating.
  • Permissive communication between the Orai N-terminus and loop2, in an isoform-specific manner, is required for channel activation.
  • These findings provide critical insights into the structural mechanisms governing CRAC channel function.