Structural And Mechanistic Insights Into Stim1-mediated Initiation Of Store Operated Calcium Entry.

Abstract

Stromal interaction molecule-1 (STIM1) activates store operated Ca2+ entry (SOCE) in response to diminished luminal Ca2+ levels. We have recently determined the solution structure of the Ca2+−sensing region of STIM1 consisting of the EF-hand and sterile α motif (SAM) domains (EF-SAM) (Stathopulos et al. Cell Oct 3rd issue, 2008). 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 Ca2+ 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 Ca2+. We provide atomic resolution insight into the molecular basis for STIM1-mediated SOCE initiation and show that the folded/unfolded state of the Ca2+ sensing region of STIM is crucial to SOCE regulation. (Supported by CIHR and CFI).