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

Abstract

Stromal interaction molecules (STIM) 1 and STIM2 are regulators of store-operated calcium (Ca2+) entry as well as basal cytoplasmic Ca2+ 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 α-motif (SAM) domains (EF-SAM), which are responsible for sensing changes in Ca2+ levels and initiating oligomerization. STIM oligomerization is a key induction step in the activation of Ca2+-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 > 70 × shorter for STIM1 EF-SAM than STIM2 under similar conditions. Urea-induced rates of unfolding for STIM1 EF-SAM are > 3 × 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 Ca2+ homeostasis and signaling. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.