STIM1 triggers a gating rearrangement at the extracellular mouth of the ORAI1 channel

Aparna Gudlur, Ariel Quintana, Yubin Zhou, Nupura Hirve, Sahasransu Mahapatra and Patrick G. Hogan ()
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Aparna Gudlur: La Jolla Institute for Allergy and Immunology
Ariel Quintana: La Jolla Institute for Allergy and Immunology
Yubin Zhou: La Jolla Institute for Allergy and Immunology
Nupura Hirve: La Jolla Institute for Allergy and Immunology
Sahasransu Mahapatra: La Jolla Institute for Allergy and Immunology
Patrick G. Hogan: La Jolla Institute for Allergy and Immunology

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: Abstract The ER-resident regulatory protein STIM1 triggers store-operated Ca2+ entry by direct interaction with the plasma membrane Ca2+ channel ORAI1. The mechanism of channel gating remains undefined. Here we establish that STIM1 gates the purified recombinant ORAI1 channel in vitro, and use Tb3+ luminescence and, separately, disulfide crosslinking to probe movements of the pore-lining helices. We show that interaction of STIM1 with the cytoplasmic face of the human ORAI1 channel elicits a conformational change near the external entrance to the pore, detectable at the pore Ca2+-binding residue E106 and the adjacent pore-lining residue V102. We demonstrate that a short nonpolar segment of the pore including V102 forms a barrier to ion flux in the closed channel, implicating the STIM1-dependent movement in channel gating. Our data explain the close coupling between ORAI1 channel gating and ion selectivity, and open a new avenue to dissect the gating, modulation and inactivation of ORAI-family channels.

Date: 2014
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DOI: 10.1038/ncomms6164

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