Oligomerization and Ca(2+)/calmodulin control binding of the ER Ca(2+)-sensors STIM1 and STIM2 to plasma membrane lipids

Ca(2+) (calcium) homoeostasis and signalling rely on physical contacts between Ca(2+) sensors in the ER (endoplasmic reticulum) and Ca(2+) channels in the PM (plasma membrane). STIM1 (stromal interaction molecule 1) and STIM2 Ca(2+) sensors oligomerize upon Ca(2+) depletion in the ER lumen, contact phosphoinositides at the PM via their cytosolic lysine (K)-rich domains, and activate Ca(2+) channels. Differential sensitivities of STIM1 and STIM2 towards ER luminal Ca(2+) have been studied but responses towards elevated cytosolic Ca(2+) concentration and the mechanism of lipid binding remain unclear. We found that tetramerization of the STIM1 K-rich domain is necessary for efficient binding to PI(4,5)P(2)-containing PM-like liposomes consistent with an oligomerization-driven STIM1 activation. In contrast, dimerization of STIM2 K-rich domain was sufficient for lipid binding. Furthermore, the K-rich domain of STIM2, but not of STIM1, forms an amphipathic α-helix. These distinct features of the STIM2 K-rich domain cause an increased affinity for PI(4,5)P(2), consistent with the lower activation threshold of STIM2 and a function as regulator of basal Ca(2+) levels. Concomitant with higher affinity for PM lipids, binding of CaM (calmodulin) inhibited the interaction of the STIM2 K-rich domain with liposomes in a Ca(2+) and PI(4,5)P(2) concentration-dependent manner. Therefore we suggest that elevated cytosolic Ca(2+) concentration down-regulates STIM2-mediated ER–PM contacts via CaM binding.