Phosphatidylserine (PS) is an anionic glycerophospholipid characterized by a diacylglycerol backbone esterified at the sn-3 position to a phosphoserine headgroup (-PO₄-CH₂CH(NH₃⁺)COO⁻). It represents approximately 5–10% of total membrane phospholipids and is predominantly localized within the inner leaflet of eukaryotic plasma membranes. Unlike zwitterionic phosphatidylcholine (PC) or neutral phosphatidylethanolamine (PE), PS carries a net negative charge at physiological pH (pI ~4), enabling Ca²⁺ bridging, protein interactions (e.g., PKC, annexins), and regulated externalization during apoptosis as an “eat-me” signal. This distinctive signaling role places PS as a critical component of the glycerophospholipid family.

Molecular Structure

Phosphatidylserine follows the classical sn-glycerol-3-phosphate framework, typically incorporating saturated fatty acids at the sn-1 position (18:0 frequently preferred) and polyunsaturated chains at sn-2 (18:1, 20:4, or 22:6 DHA, particularly enriched in brain tissue). This composition generates species such as 18:0/20:4-PS. The amino and carboxyl groups of serine confer amphoteric properties, contributing to its biochemical versatility. Structural variants include lyso-PS and plasmalogen-PS. Notably, Ca²⁺ chelation reduces the effective headgroup area (~50 Ų), promoting non-lamellar hexagonal phase formation.

Biophysical Properties

PS exhibits phase transition temperatures lower than corresponding PC analogs (e.g., 18:0/20:4-PS ~14°C). Electrostatic repulsion between anionic headgroups expands bilayer spacing (membrane thickness ~4.5 nm), facilitating curvature required for vesicle budding. Transbilayer movement (flip-flop) is enhanced by Ca²⁺ and scramblase activity, while membrane asymmetry is actively maintained through flippases such as ATP8A1 and ABC transporters. These biophysical features underline PS’s central role in membrane dynamics and cellular signaling.