Membrane Phosphatidylserine Regulates Surface Charge and Protein Localization

Abstract

Electrostatic interactions with negatively charged membranes contribute to the subcellular targeting of proteins with polybasic clusters or cationic domains. Although the anionic phospholipid phosphatidylserine is comparatively abundant, its contribution to the surface charge of individual cellular membranes is unknown, partly because of the lack of reagents to analyze its distribution in intact cells. We developed a biosensor to study the subcellular distribution of phosphatidylserine and found that it binds the cytosolic leaflets of the plasma membrane, as well as endosomes and lysosomes. The negative charge associated with the presence of phosphatidylserine directed proteins with moderately positive charge to the endocytic pathway. More strongly cationic proteins, normally associated with the plasma membrane, relocalized to endocytic compartments when the plasma membrane surface charge decreased on calcium influx.

A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity

“…This small molecule, now prepared synthetically (see SI Materials and Methods for details), has been found to have pharmacological activity in endothelial cells by inhibiting growth factor-dependent pathways and thus has emerged as a drug candidate for the treatment of cancer and macular degeneration (15,16). In the present context, our choice of studying squalamine was prompted by the observation that this molecule is able to enter eukaryotic cells and displace proteins that are bound to the cytoplasmic face of plasma membranes (17)(18)(19), suggesting that it may influence the initiation of the aggregation of α-synuclein (12). Indeed squalamine has been referred to as a "cationic lipid" (18) as it carries a net positive charge and shows a high affinity for anionic phospholipids (20) of the type that nucleates the aggregation of α-synuclein, thereby reducing the negative charge of the membrane surface to which it is bound (18,21) without significantly disrupting the integrity of lipid surfaces (18).…”

Phosphorylated K-Ras limits cell survival by blocking Bcl-xL sensitization of inositol trisphosphate receptors

“…A large body of evidence supports a model whereby the polybasic region of KRas4B contributes to membrane affinity through an electrostatic interaction with the inner leaflet of the plasma membrane (4,5,20,21). Phosphorylation of serine 181 sufficiently weakens this interaction to cause K-Ras4B to dissociate from the plasma membrane.…”

Single cell wound generates electric current circuit and cell membrane potential variations that requires calcium influx

“…Finally, recent work led by Yeung et al in 2008 showed that phospholipid dependent membrane charges borne by vesicles and plasma membranes can localize molecules such as the small GTPase based on the polybasic clusters and cationic domains of these proteins. 12 Interestingly, breaking the cell membrane is thought to lead to a massive entry of positively charged molecules and ions into the cell that could lead to the appearance of an inward electric current and cell membrane depolarization. 13 We hypothesize that single cell wounding: (i) induces an electric current; (ii) causes cell membrane depolarization; (iii) induces a calcium influx that is required for electric current and membrane potential variations.…”