Chapter title |
The STIM-Orai Pathway: Conformational Coupling Between STIM and Orai in the Activation of Store-Operated Ca2+ Entry
|
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Chapter number | 5 |
Book title |
Store-Operated Ca²⁺ Entry (SOCE) Pathways
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Published in |
Advances in experimental medicine and biology, January 2017
|
DOI | 10.1007/978-3-319-57732-6_5 |
Pubmed ID | |
Book ISBNs |
978-3-31-957731-9, 978-3-31-957732-6
|
Authors |
Robert M. Nwokonko, Xiangyu Cai, Natalia A. Loktionova, Youjun Wang, Yandong Zhou, Donald L. Gill |
Abstract |
Store-operated Ca(2+) entry fulfills a crucial role in controlling Ca(2+) signals in almost all cells. The Ca(2+)-sensing stromal interaction molecule (STIM) proteins in the endoplasmic reticulum (ER) undergo complex conformational changes in response to depleted ER luminal Ca(2+), allowing them to unfold and become trapped in ER-plasma membrane (PM) junctions. Dimers of STIM proteins trap and gate the plasma membrane Orai Ca(2+) channels within these junctions to generate discrete zones of high Ca(2+) and regulate sensitive Ca(2+)-dependent intracellular signaling pathways. The STIM-Orai activating region (SOAR) of STIM1 becomes exposed upon store depletion and promotes trapping of Orai1 at the PM. Residue Phe-394 within SOAR forms an integral part of the high-affinity Orai1-interacting site. Our results demonstrate that only a single active site within the dimeric SOAR domain of STIM1 is required for the activation of Orai1 channel activity. This unimolecular model is strongly supported by evidence of variable STIM1:Orai1 stoichiometry reported in many studies. We hypothesize that unimolecular coupling promotes cross-linking of channels, localizing Ca(2+) signals, and regulating channel activity. We have also identified a key "nexus" region in Orai1 near the C-terminal STIM1-binding site that can be mutated to constitutively activate Ca(2+) entry, mimicking STIM1 activated channels. This suggests that STIM1 mediates gating of Orai1 in an allosteric manner via interaction with the Orai1 C-terminus alone. This model suggests the dual role of STIM1 in regulating both localization and gating of Orai1 channels and has important implications for the regulation of SOCE-mediated downstream signaling and the kinetics of channel activation. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 28 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 5 | 18% |
Researcher | 4 | 14% |
Student > Doctoral Student | 3 | 11% |
Student > Master | 2 | 7% |
Professor | 1 | 4% |
Other | 3 | 11% |
Unknown | 10 | 36% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 7 | 25% |
Agricultural and Biological Sciences | 5 | 18% |
Medicine and Dentistry | 2 | 7% |
Mathematics | 1 | 4% |
Pharmacology, Toxicology and Pharmaceutical Science | 1 | 4% |
Other | 1 | 4% |
Unknown | 11 | 39% |