An apical Phe-His pair defines the Orai1-coupling site and its occlusion within STIM1.
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abstract
Ca2+ signal-generation through inter-membrane junctional coupling between endoplasmic reticulum (ER) STIM proteins and plasma membrane (PM) Orai channels, remains a vital but undefined mechanism. We identify two unusual overlapping Phe-His aromatic pairs within the STIM1 apical helix, one of which (F394-H398) mediates important control over Orai1-STIM1 coupling. In resting STIM1, this locus is deeply clamped within the folded STIM1-CC1 helices, likely near to the ER surface. The clamped environment in holo-STIM1 is critical-positive charge replacing Phe-394 constitutively unclamps STIM1, mimicking store-depletion, negative charge irreversibly locks the clamped-state. In store-activated, unclamped STIM1, Phe-394 mediates binding to the Orai1 channel, but His-398 is indispensable for transducing STIM1-binding into Orai1 channel-gating, and is spatially aligned with Phe-394 in the exposed S2 helical apex. Thus, the Phe-His locus traverses between ER and PM surfaces and is decisive in the two critical STIM1 functions-unclamping to activate STIM1, and conformational-coupling to gate the Orai1 channel.
Zhou, Y., Jennette, M. R., Ma, G., Kazzaz, S. A., Baraniak, J. H., Nwokonko, R. M., ... Gill, D. L.
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Zhou, Yandong||Jennette, Michelle R||Ma, Guolin||Kazzaz, Sarah A||Baraniak, James H||Nwokonko, Robert M||Groff, Mallary L||Velasquez-Reynel, Marcela||Huang, Yun||Wang, Youjun||Gill, Donald L