The molecular mechanism of phosphatidylserine

I. Molecular Structural Characteristics of Phosphatidylserine (PS)

Phosphatidylserine is chemically defined as 1,2-diacyl-sn-glycerol-3-phosphoserine, with structural features directly dictating its mode of membrane function regulation:

Polar Head Group: The serine moiety carries a negative charge (ionized as -COO⁻ and -NH₃⁺ at pH 7.4), forming hydrogen bonds with water molecules while binding cations (e.g., Ca²⁺) or positively charged membrane proteins via electrostatic interactions.

Hydrophobic Tail: Typically composed of 16–20 carbon fatty acid chains (e.g., palmitic acid, arachidonic acid), with at least one chain containing unsaturated bonds (cis-double bonds), endowing the molecule with flexibility.

II. Regulation of Cell Membrane Physical Properties

Phosphatidylserine influences overall membrane function by altering thermodynamic properties and microstructure:

1. Membrane Fluidity and Phase Transition Temperature

"Disturbance Effect" of Unsaturated Fatty Acids: Unsaturated fatty acid chains in PS form "kink" structures in the membrane, disrupting ordered phospholipid arrangement and lowering the phase transition temperature (e.g., pure PS membrane transitions at ~−10°C, far below lecithin’s 23°C). This maintains membrane fluidity at physiological temperature (37°C), particularly facilitating dynamic remodeling of synaptic membranes (e.g., vesicle fusion/fission).

Charge-Driven Membrane Curvature Regulation: Negative charges on PS heads repel each other, inducing local curvature when mixed with neutral phospholipids (e.g., lecithin). For instance, in the initial segment of neuronal axons, PS forms microdomains with cholesterol and sphingomyelin, regulating ion channel aggregation and activity via curvature changes.

2. Formation of Membrane Microdomains (Lipid Rafts)

PS collaborates with cholesterol and sphingomyelin to form liquid-ordered (Lo) phases, distinct from surrounding liquid-disordered (Ld) phases:

Signaling Molecule Anchoring: During T-cell activation, PS-enriched microdomains recruit T-cell receptors (TCR) and CD28 costimulatory molecules, forming signaling hubs.

Detergent Resistance: PS microdomains are insoluble in non-ionic detergents (e.g., Triton X-100), making them markers for specific functional domains in membrane isolation experiments.

III. Regulatory Mechanisms of Membrane Proteins

Phosphatidylserine regulates membrane protein function through direct binding or conformational modulation:

1. Activity Regulation of Ion Channels and Receptors

Gating Control of Ca²⁺ Channels: In cardiac myocytes, PS binds to the intracellular domain of L-type Ca²⁺ channel (Cav1.2) α1 subunit, stabilizing the open conformation via electrostatic interactions to enhance Ca²⁺ influx and regulate myocardial contraction.

Signal Transduction of G Protein-Coupled Receptors (GPCRs): The C-terminal tail of thyrotropin-releasing hormone receptor (TRHR) contains a PS-binding motif (R/K-X-K/R). Binding to PS promotes G protein coupling and activation of the downstream PLC-IP3 pathway, critical for pituitary hormone secretion.

2. Localization and Clustering of Membrane Proteins

PS as a "Molecular Anchor": The intracellular domain of platelet membrane glycoprotein GPVI has a PS-binding site (YxxL motif), anchoring it to the inner membrane to ensure rapid aggregation upon collagen stimulation, initiating platelet activation.

Clathrin-Mediated Endocytosis: The μ2 subunit of endocytic adapter protein AP-2 recognizes PS via its PH domain, mediating endocytosis of transferrin receptors. PS deficiency causes abnormal AP-2 localization, inhibiting receptor-mediated endocytosis efficiency.

IV. Functions in Membrane Dynamic Processes

Phosphatidylserine maintains cellular homeostasis by participating in membrane fusion, fission, and repair:

1. Vesicle Trafficking and Membrane Fusion

Synaptic Vesicle Exocytosis: At neuronal presynaptic membranes, PS binds to the C2 domain of synaptotagmin, mediating Ca²⁺-triggered vesicle-plasma membrane fusion. Studies show PS deficiency shortens vesicle fusion pore opening time, reducing neurotransmitter release.

Autophagosome Formation: The autophagy-related protein complex Atg5-Atg12-Atg16L localizes to autophagosomal membranes via a PS-binding domain (ALIX-like motif), promoting autophagosome elongation and closure for intracellular waste degradation.

2. Membrane Damage Repair and Apoptosis Regulation

Emergency Repair Mechanisms: When membranes are damaged by mechanical stress or toxins, PS repairs via two pathways:

Ca²⁺-dependent membrane sealing: Ca²⁺ influx at the damage site activates scramblase, flipping PS to the outer membrane, where charge attraction and hydrophobic interactions fill the damaged area.

Extracellular vesicle-mediated repair: PS-containing vesicles secreted by macrophages fuse with damaged membranes, providing phospholipid building blocks for repair.

Bidirectional Regulation of Apoptotic Signals:

Normal cells: PS is anchored to the inner membrane by ATP-dependent flippase (e.g., ATP11C), avoiding recognition by phagocytes.

Apoptotic cells: Flippase inactivation leads to PS externalization, serving as an "eat-me" signal recognized by macrophage scavenger receptors (e.g., TAM receptors) for apoptotic cell clearance. In neurons, high PS concentrations competitively inhibit pro-apoptotic proteins (e.g., Bax) from localizing to membranes, delaying apoptosis.

V. Dynamic Association Between Metabolism and Membrane Function

PS synthesis, degradation, and transmembrane transport form a dynamic network for fine-tuning membrane function:

1. Regulation of Synthetic and Degradative Pathways

Subcellular Localization of Synthases: Phosphatidylserine synthases PSS1 and PSS2 localize to mitochondria-associated membranes (MAM), with their PS products transported to the cell membrane via vesicles or phospholipid transfer proteins (e.g., StAR), ensuring precise local PS concentration control.

Spatiotemporal Actions of Phospholipases: Phospholipase D2 (PLD2) specifically hydrolyzes PS in caveolae to produce phosphatidic acid (PA), which acts as a second messenger to activate mTORC1 signaling for cell growth regulation. Phospholipase A2 (PLA2) hydrolyzes PS to release arachidonic acid, involved in inflammatory signal generation.

2. Functional Significance of Transmembrane Flipping

Asymmetric PS distribution (80%–90% in the inner leaflet) relies on dynamic flippase and scramblase activity:

Signal Activation: During platelet activation, Ca²⁺-activated scramblase flips PS to the membrane surface, providing binding sites for coagulation factors V and X to initiate the coagulation cascade.

Membrane Potential Maintenance: Inner-leaflet PS localization in red blood cells prevents excessive surface negative charge accumulation, avoiding erythrocyte adhesion and hemolysis.

VI. Dysfunction in Pathological States

Disruption of PS molecular mechanisms links to multiple diseases:

Alzheimer’s Disease: Mutations in phosphatidylserine synthase genes reduce PS levels, impairing Aβ protein clearance and promoting amyloid plaque formation.

Cardiovascular Diseases: Increased PS externalization in endothelial cells activates the coagulation system, promoting thrombosis.

Immune Disorders: Abnormal PS recognition receptors (e.g., TIM-4) cause defective apoptotic cell clearance, triggering systemic lupus erythematosus (SLE).

Phosphatidylserine regulates cell membrane function at three levels—physical properties, protein modulation, and membrane dynamics—via its unique molecular structure. This regulation is not isolated but highly coupled with PS metabolic networks, transmembrane distribution, and cellular microenvironments, forming a precise molecular mechanism network. Deepening our understanding of PS-mediated membrane regulation not only provides targets for parsing pathologies like neurological disorders and immune dysfunctions but also lays a theoretical foundation for developing PS-based drug delivery systems (e.g., PS-modified liposomes) and functional foods (e.g., PS supplements).