Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Calcium directly regulates phosphatidylinositol 4,5-Bbsphosphate headgroup conformation and recognition.
J. Am. Chem. Soc. 139, 4019-4024 (2017)
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 sphosphate (PI(4,5)P-2), the main lipid marker of the plasma membrane. Electrokinetic potential measurements of PI(4,5)P-2 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)P-2 lipid sensor, phospholipase C delta 1 pleckstrin homology domain (PLC delta 1-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)P-2 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 delta 1-PH and PI(4,5)P-2, 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.
Zusatzinfos bearbeiten [➜Einloggen]
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Molecular-dynamics Simulations; Pleckstrin Homology Domain; Local Ph Modulation; Intracellular Magnesium; Phospholipid-membranes; Cluster Formation; Lipid-bilayers; High-affinity; Air-water; Binding
ISSN (print) / ISBN 0002-7863
Zeitschrift Journal of the American Chemical Society
Quellenangaben Band: 139, Heft: 11, Seiten: 4019-4024
Verlag American Chemical Society (ACS)
Begutachtungsstatus Peer reviewed
Institut(e) Institute for Pancreatic Beta Cell Research (IPI)