Calcium Directly Regulates Phosphatidylinositol 4,5-Bisphosphate Headgroup Conformation and Recognition.
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)P2containing 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)P2lipid 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)P2headgroup 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.
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.|German Center for Diabetes Research (DZD e.V.) , Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
Eva
E
Bilkova
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic , Flemingovo náměstí 2, 16610 Prague 6, Czech Republic.|Institute of Experimental Botany, Academy of Sciences of the Czech Republic , v.v.i., Rozvojová 263, 16502 Prague 6, Czech Republic.
Roman
R
Pleskot
Department of Physics, Tampere University of Technology , P.O. Box 692, FI-33101 Tampere, Finland.
Sami
S
Rissanen
Simou
S
Sun
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.|Laboratory of Cytobiochemistry, Faculty of Biotechnology, University of Wrocław , Joliot-Curie 14a, 50-383 Wrocław, Poland.
Aleksander
A
Czogalla
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.
Lukasz
L
Cwiklik
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.
Tomasz
0000-0001-6765-7013
T
Róg
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.|MEMPHYS- Center for Biomembrane Physics, University of Southern Denmark , DK-5230 Odense, Denmark.
Ilpo
0000-0001-7408-3214
I
Vattulainen
Paul S
0000-0002-8524-0438
PS
Cremer
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic , Flemingovo náměstí 2, 16610 Prague 6, Czech Republic.|Department of Physics, Tampere University of Technology , P.O. Box 692, FI-33101 Tampere, Finland.
Pavel
0000-0002-6892-3288
P
Jungwirth
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.|German Center for Diabetes Research (DZD e.V.) , Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
Ünal
0000-0003-4375-3144
Ü
Coskun
D002118:Calcium / Q000737:chemistry / Q000378:metabolism*; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry / Q000378:metabolism*
D019269:Phosphatidylinositol 4,5-Diphosphate; D002118:Calcium