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Sci. Signal., 16 November 2010
Vol. 3, Issue 148, p. ra82
[DOI: 10.1126/scisignal.2001122]

RESEARCH ARTICLES

Activation of STIM1-Orai1 Involves an Intramolecular Switching Mechanism

Marek K. Korzeniowski1, Isabel Martín Manjarrés2, Peter Varnai3, and Tamas Balla1*

1 Section on Molecular Signal Transduction, Program for Developmental Neuroscience, National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.
2 Instituto de Biologia y Genetica Molecular, University of Valladolid–Consejo Superior de Investigaciones Científicas, C/Sanz y Forés s/n, 47003 Valladolid, Spain.
3 Department of Physiology, Faculty of Medicine, Semmelweis University, 1094 Budapest, Hungary.

Abstract: Stromal interaction molecule 1 (STIM1) stimulates calcium ion (Ca2+) entry through plasma membrane Orai1 channels in response to decreased Ca2+ concentrations in the endoplasmic reticulum lumen. We identified an acidic motif within the STIM1 coiled-coil region that keeps its Ca2+ activation domain [Ca2+ release–activated Ca2+ (CRAC) activation domain/STIM1-Orai activating region (CAD/SOAR)]—a cytoplasmic region required for its activation of Orai1—inactive. The sequence of the STIM1 acidic motif shows substantial similarity to that of the carboxyl-terminal coiled-coil segment of Orai1, which is the postulated site of interaction with STIM1. Mutations within this acidic region rendered STIM1 constitutively active, whereas mutations within a short basic segment of CAD/SOAR prevented Orai1 activation. We propose that the CAD/SOAR domain is released from an intramolecular clamp during STIM1 activation, allowing the basic segment to activate Orai1 channels. This evolutionarily conserved mechanism of STIM1 activation resembles the regulation of protein kinases by intramolecular silencing through pseudosubstrate binding.

* To whom correspondence should be addressed. E-mail: ballat{at}mail.nih.gov

Citation: M. K. Korzeniowski, I. M. Manjarrés, P. Varnai, T. Balla, Activation of STIM1-Orai1 Involves an Intramolecular Switching Mechanism. Sci. Signal. 3, ra82 (2010).

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