The orchestrated recognition of phosphoinositides and concomitant intracellular release of Ca2+ is pivotal to almost every aspect of cellular processes, including membrane homeostasis, cell division and growth, vesicle trafficking, as well as secretion. Although Ca2+ is known to directly impact phosphoinositide clustering, little is known about the molecular basis for this or its significance in cellular signaling. Here, we study the direct interaction of Ca2+ with phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), the main lipid marker of the plasma membrane. Electrokinetic potential measurements of PI(4,5)P2 containing liposomes reveal that Ca2+ as well as Mg2+ reduce the zeta potential of liposomes to nearly background levels of pure phosphatidylcholine membranes. Strikingly, lipid recognition by the default PI(4,5)P2 lipid sensor, phospholipase C delta 1 pleckstrin homology domain (PLC δ1-PH), is completely inhibited in the presence of Ca2+, while Mg2+ has no effect with 100 nm liposomes and modest effect with giant unilamellar vesicles. Consistent with biochemical data, vibrational sum frequency spectroscopy and atomistic molecular dynamics simulations reveal how Ca2+ binding to the PI(4,5)P2 headgroup and carbonyl regions leads to confined lipid headgroup tilting and conformational rearrangements. We rationalize these findings by the ability of calcium to block a highly specific interaction between PLC δ1-PH and PI(4,5)P2, encoded within the conformational properties of the lipid itself. Our studies demonstrate the possibility that switchable phosphoinositide conformational states can serve as lipid recognition and controlled cell signaling mechanisms.

Department of Physics Tampere University of Technology P O Box 692 FI 33101 Tampere Finland

Department of Physics University of Helsinki P O Box 64 FI 00014 Helsinki Finland

German Center for Diabetes Research Ingolstädter Landstraße 1 85764 Neuherberg Germany

Institute of Experimental Botany Academy of Sciences of the Czech Republic v v i Rozvojová 263 16502 Prague 6 Czech Republic

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic Flemingovo náměstí 2 16610 Prague 6 Czech Republic

J Heyrovský Institute of Physical Chemistry Academy of Sciences of the Czech Republic v v i Dolejskova 3 18223 Prague 8 Czech Republic

Laboratory of Cytobiochemistry Faculty of Biotechnology University of Wrocław Joliot Curie 14a 50 383 Wrocław Poland

MEMPHYS Center for Biomembrane Physics University of Southern Denmark DK 5230 Odense Denmark

Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden Technische Universität Dresden Fetscher Strasse 74 01307 Dresden Germany

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