title: Oligomerization and Ca2+/calmodulin control binding of the ER Ca2+-sensors STIM1 and STIM2 to plasma membrane lipids.
abstract: Ca2+ (calcium) homoeostasis and signalling rely on physical contacts between Ca2+ sensors in the ER (endoplasmic reticulum) and Ca2+ channels in the PM (plasma membrane). STIM1 (stromal interaction molecule 1) and STIM2 Ca2+ sensors oligomerize upon Ca2+ depletion in the ER lumen, contact phosphoinositides at the PM via their cytosolic lysine (K)-rich domains, and activate Ca2+ channels. Differential sensitivities of STIM1 and STIM2 towards ER luminal Ca2+ have been studied but responses towards elevated cytosolic Ca2+ 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)P2-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)P2, consistent with the lower activation threshold of STIM2 and a function as regulator of basal Ca2+ 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 Ca2+ and PI(4,5)P2 concentration-dependent manner. Therefore we suggest that elevated cytosolic Ca2+ concentration down-regulates STIM2-mediated ER-PM contacts via CaM binding.
authors.affiliation: *Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, University of Heidelberg, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Bhardwaj
authors.affiliation: †Heidelberg University Biochemistry Center, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.
authors.forename: Hans-Michael
authors.initials: HM
authors.lastname: Müller
authors.affiliation: †Heidelberg University Biochemistry Center, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Nickel
authors.affiliation: *Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, University of Heidelberg, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Seedorf
mesh_terms: D001665:Binding Sites; D001667:Binding, Competitive; D002118:Calcium / Q000737:chemistry; D002147:Calmodulin / Q000737:chemistry; D015815:Cell Adhesion Molecules / Q000737:chemistry*; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D008563:Membrane Lipids; D008565:Membrane Proteins / Q000737:chemistry*; D009363:Neoplasm Proteins / Q000737:chemistry*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2
chemical_list: D002147:Calmodulin; D015815:Cell Adhesion Molecules; D008081:Liposomes; D008563:Membrane Lipids; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; C103530:STIM1 protein, human; C513279:STIM2 protein, human; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D002118:Calcium
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