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

Author

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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)

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.

Suggested Citation

  • 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 & Donald L. Gill, 2023. "An apical Phe-His pair defines the Orai1-coupling site and its occlusion within STIM1," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42254-x
    DOI: 10.1038/s41467-023-42254-x
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    References listed on IDEAS

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    1. Yandong Zhou & Xiangyu Cai & Natalia A. Loktionova & Xianming Wang & Robert M. Nwokonko & Xizhuo Wang & Youjun Wang & Brad S. Rothberg & Mohamed Trebak & Donald L. Gill, 2016. "The STIM1-binding site nexus remotely controls Orai1 channel gating," Nature Communications, Nature, vol. 7(1), pages 1-13, December.
    2. Ruth A. Pumroy & Anna D. Protopopova & Tabea C. Fricke & Iris U. Lange & Ferdinand M. Haug & Phuong T. Nguyen & Pamela N. Gallo & Bárbara B. Sousa & Gonçalo J. L. Bernardes & Vladimir Yarov-Yarovoy & , 2022. "Structural insights into TRPV2 activation by small molecules," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Guolin Ma & Lian He & Shuzhong Liu & Jiansheng Xie & Zixian Huang & Ji Jing & Yi-Tsang Lee & Rui Wang & Hesheng Luo & Weidong Han & Yun Huang & Yubin Zhou, 2020. "Optogenetic engineering to probe the molecular choreography of STIM1-mediated cell signaling," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    4. Peter B. Stathopulos & Rainer Schindl & Marc Fahrner & Le Zheng & Geneviève M. Gasmi-Seabrook & Martin Muik & Christoph Romanin & Mitsuhiko Ikura, 2013. "STIM1/Orai1 coiled-coil interplay in the regulation of store-operated calcium entry," Nature Communications, Nature, vol. 4(1), pages 1-12, December.
    5. Guolin Ma & Ming Wei & Lian He & Chongxu Liu & Bo Wu & Shenyuan L. Zhang & Ji Jing & Xiaowen Liang & Alessandro Senes & Peng Tan & Siwei Li & Aomin Sun & Yunchen Bi & Ling Zhong & Hongjiang Si & Yuequ, 2015. "Inside-out Ca2+ signalling prompted by STIM1 conformational switch," Nature Communications, Nature, vol. 6(1), pages 1-14, November.
    6. Marc Fahrner & Michael Stadlbauer & Martin Muik & Petr Rathner & Peter Stathopulos & Mitsu Ikura & Norbert Müller & Christoph Romanin, 2018. "A dual mechanism promotes switching of the Stormorken STIM1 R304W mutant into the activated state," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    7. Yandong Zhou & Xizhuo Wang & Xianming Wang & Natalia A. Loktionova & Xiangyu Cai & Robert M. Nwokonko & Erin Vrana & Youjun Wang & Brad S. Rothberg & Donald L. Gill, 2015. "STIM1 dimers undergo unimolecular coupling to activate Orai1 channels," Nature Communications, Nature, vol. 6(1), pages 1-10, December.
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