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A dual mechanism promotes switching of the Stormorken STIM1 R304W mutant into the activated state

Author

Listed:
  • Marc Fahrner

    (Johannes Kepler University Linz)

  • Michael Stadlbauer

    (Johannes Kepler University Linz)

  • Martin Muik

    (Johannes Kepler University Linz)

  • Petr Rathner

    (Johannes Kepler University Linz)

  • Peter Stathopulos

    (University of Western Ontario)

  • Mitsu Ikura

    (University Health Network
    University of Toronto)

  • Norbert Müller

    (Johannes Kepler University Linz
    University of South Bohemia)

  • Christoph Romanin

    (Johannes Kepler University Linz)

Abstract

STIM1 and Orai1 are key components of the Ca2+-release activated Ca2+ (CRAC) current. Orai1, which represents the subunit forming the CRAC channel complex, is activated by the ER resident Ca2+ sensor STIM1. The genetically inherited Stormorken syndrome disease has been associated with the STIM1 single point R304W mutant. The resulting constitutive activation of Orai1 mainly involves the CRAC-activating domain CAD/SOAR of STIM1, the exposure of which is regulated by the molecular interplay between three cytosolic STIM1 coiled-coil (CC) domains. Here we present a dual mechanism by which STIM1 R304W attains the pathophysiological, constitutive activity eliciting the Stormorken syndrome. The R304W mutation induces a helical elongation within the CC1 domain, which together with an increased CC1 homomerization, destabilize the resting state of STIM1. This culminates, even in the absence of store depletion, in structural extension and CAD/SOAR exposure of STIM1 R304W leading to constitutive CRAC channel activation and Stormorken disease.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03062-w
    DOI: 10.1038/s41467-018-03062-w
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    Cited by:

    1. 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.

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