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STIM1 Clusters and Activates CRAC Channels via Direct Binding of a Cytosolic Domain to Orai1
Open accessAbstract
SUMMARY Store-operated Ca2+ channels activated by the depletion of Ca2+ from the endoplasmic reticulum (ER) are a major Ca2+ entry pathway in non-excitable cells and are essential for T cell activation and adaptive immunity. Following store depletion, the ER Ca2+ sensor STIM1 and the CRAC channel protein Orai1 redistribute to ER-plasma membrane (PM) junctions, but the fundamental issue of how STIM1 activates the CRAC channel at these sites is unresolved. Here we identify a minimal, highly conserved 107-aa CRAC activation domain (CAD) of STIM1 that binds directly to the N- and C-termini of Orai1 to open the CRAC channel. Purified CAD forms a tetramer that clusters CRAC channels, but analysis of STIM1 mutants reveals that channel clustering is not sufficient for channel activation. These studies establish a molecular mechanism for store-operated Ca2+ entry in which the direct binding of STIM1 to Orai1 drives the accumulation and the activation of CRAC channels at ER-PM junctions.
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Cites
Store-Operated Calcium Channels
Parekh, A. B., & Putney, J. W. (2005) · Physiological Reviews · doi:10.1152/physrev.00057.2003 · Cited by 2,089
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Hogan, P. G., Lewis, R. S., & Rao, A. (2010) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132550 · Cited by 760
Self-citationOrganization and Function of Membrane Contact Sites
Helle, S. C. J., Kanfer, G., Kolar, K., Lang, A., Michel, A. H., & Kornmann, B. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.01.028 · Cited by 453
Ion channels and transporters in lymphocyte function and immunity
Feske, S., Skolnik, E. Y., & Prakriya, M. (2012) · Nature Reviews Immunology · doi:10.1038/nri3233 · Cited by 441
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Metadata
- Authors
- Park, C. Y., Hoover, P. J., Mullins, F. M., Bachhawat, P., Covington, E. D., Raunser, S., Walz, T., Garcia, K. C., Dolmetsch, R. E., & Lewis, R. S.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2009-03
- Volume
- 136
- Issue
- 5
- Pages
- 876-890
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2133603157
- Cited by
- 954
- References
- 1
- FWCI
- 37.37
- Type
- journal article
- Language
- en
- Open access
- bronze
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- The paper
- Park, C. Y., Hoover, P. J., Mullins, F. M., Bachhawat, P., Covington, E. D., Raunser, S., Walz, T., Garcia, K. C., Dolmetsch, R. E., & Lewis, R. S. (2009). STIM1 Clusters and Activates CRAC Channels via Direct Binding of a Cytosolic Domain to Orai1. Cell. https://doi.org/10.1016/j.cell.2009.02.014
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