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PLoS Biol. 2018 Nov 16;16(11):e2006898. doi: 10.1371/journal.pbio.2006898. eCollection 2018 Nov.

Identification of molecular determinants that govern distinct STIM2 activation dynamics.

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Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing, P. R. China.
Center for Translational Cancer Research, Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, Texas, United States of America.
Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, P. R. China.
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey Pennsylvania, United States of America.
Kuang Yaming Honors School, Nanjing University, Nanjing, P. R. China.
Department of Medical Physiology, College of Medicine, Texas A&M University, Temple, Texas, United States of America.


The endoplasmic reticulum (ER) Ca2+ sensors stromal interaction molecule 1 (STIM1) and STIM2, which connect ER Ca2+ depletion with extracellular Ca2+ influx, are crucial for the maintenance of Ca2+ homeostasis in mammalian cells. Despite the recent progress in unraveling the role of STIM2 in Ca2+ signaling, the mechanistic underpinnings of its activation remain underexplored. We use an engineering approach to direct ER-resident STIMs to the plasma membrane (PM) while maintaining their correct membrane topology, as well as Förster resonance energy transfer (FRET) sensors that enabled in cellulo real-time monitoring of STIM activities. This allowed us to determine the calcium affinities of STIM1 and STIM2 both in cellulo and in situ, explaining the current discrepancies in the literature. We also identified the key structural determinants, especially the corresponding G residue in STIM1, which define the distinct activation dynamics of STIM2. The chimeric E470G mutation could switch STIM2 from a slow and weak Orai channel activator into a fast and potent one like STIM1 and vice versa. The systemic dissection of STIM2 activation by protein engineering sets the stage for the elucidation of the regulation and function of STIM2-mediated signaling in mammals.

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