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J Biol Chem. 2009 Jan 9;284(2):728-32. doi: 10.1074/jbc.C800178200. Epub 2008 Nov 19.

Stromal interaction molecule (STIM) 1 and STIM2 calcium sensing regions exhibit distinct unfolding and oligomerization kinetics.

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Division of Signaling Biology, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.


Stromal interaction molecules (STIM) 1 and STIM2 are regulators of store-operated calcium (Ca(2+)) entry as well as basal cytoplasmic Ca(2+) levels in human cells. Despite a high sequence similarity (>65%) and analogous sequence-based domain architectures, STIM1 and STIM2 differentially influence these phenomena. Among all eukaryotes, the endoplasmic reticulum luminal portion of STIM proteins minimally encode EF-hand and sterile alpha-motif (SAM) domains (EF-SAM), which are responsible for sensing changes in Ca(2+) levels and initiating oligomerization. STIM oligomerization is a key induction step in the activation of Ca(2+)-permeable channels on the plasma membrane. Here, we show that the kinetic half-time of conversion from a monomeric to a steady oligomeric state is >70x shorter for STIM1 EF-SAM than STIM2 under similar conditions. Urea-induced rates of unfolding for STIM1 EF-SAM are >3x quicker when compared with STIM2, coherent with partial unfolding-coupled aggregation. Additionally, we demonstrate that the isoform-specific N-terminal residues beyond EF-SAM can influence the stability of this region. We postulate that distinct oligomerization dynamics of STIM isoforms have evolved to adapt to differential roles in Ca(2+) homeostasis and signaling.

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