Structural and mechanistic insights into STIM1-mediated initiation of store-operated calcium entry

Cell. 2008 Oct 3;135(1):110-22. doi: 10.1016/j.cell.2008.08.006.


Stromal interaction molecule-1 (STIM1) activates store-operated Ca2+ entry (SOCE) in response to diminished luminal Ca2+ levels. Here, we present the atomic structure of the Ca2+-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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calcium Signaling / genetics
  • DNA Mutational Analysis
  • EF Hand Motifs
  • HeLa Cells
  • Humans
  • Membrane Proteins / chemistry*
  • Membrane Proteins / metabolism*
  • Models, Molecular
  • Molecular Sequence Data
  • Neoplasm Proteins / chemistry*
  • Neoplasm Proteins / metabolism*
  • Nuclear Magnetic Resonance, Biomolecular
  • Sequence Alignment
  • Stromal Interaction Molecule 1


  • Membrane Proteins
  • Neoplasm Proteins
  • STIM1 protein, human
  • Stromal Interaction Molecule 1

Associated data

  • PDB/2K60