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J. Biol. Chem., Vol. 282, Issue 40, 29678-29690, October 5, 2007

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Visualization and Manipulation of Plasma Membrane-Endoplasmic Reticulum Contact Sites Indicates the Presence of Additional Molecular Components within the STIM1-Orai1 Complex^*

Péter Várnai¹, Balázs Tóth, Dániel J. Tóth, László Hunyady, and Tamas Balla²

From the Section on Molecular Signal Transduction, NICHD, National Institutes of Health, Bethesda, Maryland 20892-4510 and the Department of Physiology, Semmelweis University, School of Medicine, Budapest, Hungary, H-1086

STIM1, a recently identified endoplasmic reticulum (ER) protein, rapidly translocates to a plasma membrane-adjacent ER compartment upon depletion of the ER Ca²⁺ stores. Here we use a novel means, namely a chemically inducible bridge formation between the plasma and ER membranes, to highlight the plasma membrane-adjacent ER compartment and show that this is the site where STIM1 and its Ca²⁺ channel partner, Orai1, form a productive interaction upon store depletion. By changing the length of the linkers connecting the plasma and ER membranes, we show that Orai1 requires a larger space than STIM1 between the two membranes. This finding suggests that Orai1 is part of a larger macromolecular cluster with an estimated 11-14-nm protrusion to the cytoplasm, whereas the cytoplasmic domain of STIM1 fits in a space calculated to be less than 6 nm. We finally show that agonist-induced translocation of STIM1 is rapidly reversible and only partially affects STIM1 in the juxtanuclear ER compartment. These studies are the first to detect juxtaposed areas between the ER and the plasma membrane in live cells, revealing novel details of STIM1-Orai1 interactions.

Received for publication, May 25, 2007 , and in revised form, July 6, 2007.

^* This work was supported in part by the Intramural Research Program of the National Institute of Child Health and Human Development of the National Institutes of Health (to B. T., P. V., and T. B.) and by an appointment of PV to the Senior Fellowship Program at the NIH. This latter program is administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains three supplemental figures and three movies.

This article was selected as a Paper of the Week.

¹ A Bolyai Fellow of the Hungarian Academy of Science. Supported by the Hungarian Scientific Research fund (Grant OTKA NF-68563) and the Medical Research Council (Grant ETT 440/2006).

² To whom correspondence should be addressed: National Institutes of Health, Bldg. 49, Rm. 6A35, 49 Convent Dr., Bethesda, MD 20892-4510. Tel.: 301-496-2136; Fax: 301-480-8010; E-mail: ballat{at}mail.nih.gov.

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