Cations induce shape remodeling of negatively charged phospholipid membranes

Abstract

The divalent cation Ca2+ is a key component in many cell signaling and membrane trafficking pathways. Ca2+ signal transduction commonly occurs through interaction with protein partners. However, in this study we show a novel mechanism by which Ca2+ may impact membrane structure. We find an asymmetric concentration of Ca2+ across the membrane triggers deformation of membranes containing negatively charged lipids such as Phosphatidylserine (PS) and Phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2). Membrane invaginations in vesicles were observed forming away from the leaflet with higher Ca2+ concentration, showing that Ca2+ induces negative curvature. We hypothesize that the negative curvature is produced by Ca2+-induced clustering of PS and PI(4,5)P2. In support of this notion, we find that Ca2+-induced membrane deformation is stronger for membranes containing PI(4,5)P2, which is known to more readily cluster in the presence of Ca2+. The observed Ca2+-induced membrane deformation is strongly influenced by Na+ ions. A high symmetric [Na+] across the membrane reduces Ca2+ binding by electrostatic shielding, inhibiting Ca2+-induced membrane deformation. An asymmetric [Na+] across the membrane, however, can either oppose or support Ca2+-induced deformation, depending on the direction of the gradient in [Na+]. At a sufficiently high asymmetric Na+ concentration it can impact membrane structure in the absence of Ca2+. We propose that Ca2+ works in concert with curvature generating proteins to modulate membrane curvature and shape transitions. This novel structural impact of Ca2+ could be important for Ca2+-dependent cellular processes that involve the creation of membrane curvature, including exocytosis, invadopodia, and cell motility.

Contactless Stimulation and Control of Biomimetic Nanotubes by Calcium Ion Gradients

“…These invaginations continued to increase in size over time upon injection of calcium ions filling the interior of the bulge, Figure A‐2–A‐7. Both membrane invaginations and tubular protrusions were previously reported in GUVs exposed to external stimuli, such as polymers, calcium ions, pH gradient, osmotic stress, proteins, and polypeptides . The observed invaginations presented herein, are reminiscent to those reported in our previous work on the tubulation within GUVs upon binding of calcium ions .…”

K-Ras G-domain binding with signaling lipid phosphatidylinositol (4,5)-phosphate (PIP2): membrane association, protein orientation, and function

“…73) and the A2A GPCR (74)). Calcium is known to bind to some small GTPases (75) but also causes a clustering of PIP2 (76,77).…”

Membrane curvature allosterically regulates the phosphatidylinositol cycle, controlling its rate and acyl-chain composition of its lipid intermediates

“…In particular, we have identified two types of lipid structures that allosterically regulate the enzyme activity and acyl-chain specificity: the cubic phase and membrane fusion intermediates. Cubic phases in zwitterionic membranes and membrane fusion intermediates in PS-Ca 2ϩ mixtures have little in common with each other, except that they both form similar kinds of highly bent structures (47,48). These bent structures correspond to regions of certain cubic phases that allow the joining of one unit cell with another or, in the case of PS-Ca 2ϩ , that forms the fusion pore between bilayers.…”