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Calcium directly regulates phosphatidylinositol 4,5-Bbsphosphate headgroup conformation and recognition.
J. Am. Chem. Soc. 139, 4019-4024 (2017)
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DOI
PMC
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.
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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
e-ISSN
1520-5126
Zeitschrift
Journal of the American Chemical Society
Quellenangaben
Band: 139,
Heft: 11,
Seiten: 4019-4024
Verlag
American Chemical Society (ACS)
Verlagsort
Washington
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute for Pancreatic Beta Cell Research (IPI)