Structural and Mechanistic Insights into STIM1-Mediated Initiation of Store-Operated Calcium Entry

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2008.08.006 Byline: Peter B. Stathopulos (1), Le Zheng (1), Guang-Yao Li (1), Michael J. Plevin (1), Mitsuhiko Ikura (1) Keywords: CELLBIO Abstract: Stromal interaction molecule-1 (STIM1) activates store-operated Ca.sup.2+ entry (SOCE) in response to diminished luminal Ca.sup.2+ levels. Here, we present the atomic structure of the Ca.sup.2+-sensing region of STIM1 consisting of the EF-hand and sterile [alpha] motif (SAM) domains (EF-SAM). The canonical EF-hand is paired with a previously unidentified EF-hand. Together, the EF-hand pair mediates mutually indispensable hydrophobic interactions between the EF-hand and SAM domains. Structurally critical mutations in the canonical EF-hand, 'hidden' EF-hand, or SAM domain disrupt Ca.sup.2+ sensitivity in oligomerization via destabilization of the entire EF-SAM entity. In mammalian cells, EF-SAM destabilization mutations within full-length STIM1 induce punctae formation and activate SOCE independent of luminal Ca.sup.2+. We provide atomic resolution insight into the molecular basis for STIM1-mediated SOCE initiation and show that the folded/unfolded state of the Ca.sup.2+-sensing region of STIM is crucial to SOCE regulation. Author Affiliation: (1) Division of Signaling Biology, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto Medical Discovery Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada Article History: Received 10 March 2008; Revised 26 May 2008; Accepted 1 August 2008 Article Note: (miscellaneous) Published: October 2, 2008