An apical Phe-His pair defines the Orai1-coupling site and its occlusion within STIM1

Yandong Zhou (), Michelle R. Jennette, Guolin Ma, Sarah A. Kazzaz, James H. Baraniak, Robert M. Nwokonko, Mallary L. Groff, Marcela Velasquez-Reynel, Yun Huang, Youjun Wang and Donald L. Gill ()
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Yandong Zhou: The Pennsylvania State University College of Medicine
Michelle R. Jennette: The Pennsylvania State University College of Medicine
Guolin Ma: Texas A&M University
Sarah A. Kazzaz: The Pennsylvania State University College of Medicine
James H. Baraniak: The Pennsylvania State University College of Medicine
Robert M. Nwokonko: Stanford University School of Medicine
Mallary L. Groff: The Pennsylvania State University College of Medicine
Marcela Velasquez-Reynel: The Pennsylvania State University College of Medicine
Yun Huang: Texas A&M University
Youjun Wang: Beijing Normal University
Donald L. Gill: The Pennsylvania State University College of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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 Sα2 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.

Date: 2023
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DOI: 10.1038/s41467-023-42254-x

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