#membrane asymmetry

Plasma Membrane

Which of the following phospholipids is most abundant in the outer leaflet of the plasma membrane?

Quantitative lipidomics using phospholipase treatment, chemical labeling, and mass spectrometry shows outer leaflet of mammalian plasma membrane is dominated by choline-containing lipids: phosphatidylcholine roughly 60% of outer phospholipid and sphingomyelin nearly exclusively outer, together creating relatively neutral, saturated, raft-competent surface that interacts with extracellular environment and immune system. Their cylindrical shape stabilizes flat outer leaflet and protects from opsonization by complement. In contrast phosphatidylserine and phosphatidylethanolamine concentrate 75 to 90% in inner leaflet facing cytosol where their anionic and conical properties facilitate generation of negative curvature for endocytosis, binding of polycationic domains of Ras and annexins including annexin A2, and support for protein kinase C activation. Phosphatidylinositol and its phosphorylated derivatives also inner, providing platform for cytoskeleton attachment via ERM proteins and clathrin adaptors. Cardiolipin with four acyl chains is signature of inner mitochondrial membrane where it binds respiratory complexes, absent from plasma membrane. Therefore phosphatidylcholine outer enrichment reflects active sorting by P4-ATPases and thermodynamic preference, essential for charge asymmetry and signaling integrity.

Ref: Alberts et al., Molecular Biology of the Cell, 7th ed., Chapter 10: Outer Leaflet Enrichment of PC.

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Plasma Membrane

Which of the following best describes lipid bilayer asymmetry?

Transverse asymmetry arises because lipid synthesis and active transport are polarized across bilayer and maintained continuously by energy-dependent enzymes. In ER, phosphatidylcholine is produced by CDP-choline pathway and partly enriches outer leaflet after vesicular trafficking, while phosphatidylserine synthesized by serine exchange enzymes PSS1 and PSS2 remains preferentially cytosolic. P4-ATPase flippases ATP11C and ATP8A1 hydrolyze ATP to move phosphatidylserine and phosphatidylethanolamine inward against gradient, while ABC floppases like ABCB4 and ABCC1 move phosphatidylcholine and cholesterol outward, and calcium-activated scramblases randomize quickly upon activation. Consequently phosphatidylcholine and sphingomyelin are about 60-75% outer, phosphatidylserine greater than 80% inner, phosphatidylethanolamine similarly inner, glycolipids exclusively outer. This selective asymmetry provides crucial functional cues: inner anionic phosphatidylserine binds polybasic motifs of K-Ras, protein kinase C, and synaptotagmin regulating membrane recruitment and exocytosis, while exposed phosphatidylserine signals engulfment or coagulation. Identical leaflet composition would erase electrochemical asymmetry, highlighting that asymmetry is actively maintained essential property for signaling, not random distribution.

Ref: Alberts et al., Molecular Biology of the Cell, 7th ed., Chapter 10: Lipid Asymmetry and Flippases.

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Properties of Plasma Membrane

Which of the following is NOT involved in maintaining plasma membrane asymmetry?

Maintenance of nonrandom phospholipid distribution across leaflets relies on specialized lipid translocators rather than hydrolytic enzymes. Flippases are P4 ATPases such as ATP11C and ATP11A complexed with CDC50A chaperone that consume ATP to move phosphatidylserine and phosphatidylethanolamine inward against gradient maintaining inner negativity. Floppases are ABC transporters ABCA1 ABCB1 ABCB4 that export phosphatidylcholine and cholesterol outward crucial for HDL biogenesis and bile secretion. Scramblases like TMEM16F ANO6 and Xkr8 family are calcium activated or caspase activated providing bidirectional nonselective pathways randomizing composition during platelet coagulation and apoptosis for phagocytosis. These activities are probed with NBD labeled phosphatidylserine internalization assays N ethylmaleimide inhibition and ionomycin calcium triggering. Lipases including phospholipase A2 cleaving sn two acyl, PLC hydrolyzing PIP2 to DAG IP3, PLD generating PA are catabolic signaling enzymes altering lipid identity but not transporting intact lipid across bilayer. Hence lipase unrelated to asymmetry maintenance distinguishing translocation from hydrolysis preventing confusion interpreting knockout phenotypes and drug targets in cell biology.

Ref: Pomorski & Menon, Annual Review Cell Biology, Lipid translocators flippase floppase scramblase functions.

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Properties of Plasma Membrane

Which of the following is responsible for the asymmetry of the lipid bilayer?

Asymmetry generation and maintenance underlie plasma membrane functional identity. Compositional asymmetry means outer leaflet enriched phosphatidylcholine sphingomyelin contributing saturated chains stability and interaction with extracellular proteins, inner leaflet enriched phosphatidylethanolamine phosphatidylserine phosphatidylinositol providing anionic surface negative charge minus one for PS PI at neutral pH recruiting peripheral proteins with polybasic patches K-Ras, C2 domains of protein kinase C, annexins bridging via calcium. Glycolipids glycosphingolipids exclusively exoplasmic presenting ABO antigens and gangliosides for recognition. Origin during synthesis requires selective transport: P4-ATPase flippases inward ATP dependent, ABC floppases outward ATP dependent, scramblases randomization calcium activated during apoptosis externalizing PS as eat-me signal for phagocytes and procoagulant surface for tenase prothrombinase assembly. Equal distribution would abolish signaling potential and lectin recognition. Cholesterol flips rapidly but does not generate asymmetry alone. Different lipid compositions between leaflets therefore cause asymmetry essential for curvature, budding, apoptosis recognition and signal transduction polarity. Maintenance involves continuous ATP consumption counteracting spontaneous scrambling tendency, highlighting energy dependence of plasma membrane identity and signaling competence.

Ref: van Meer et al., Membrane Lipid Asymmetry and Biology, Nature Reviews Mol Cell Biol 2008.

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Plasma Membrane Proteins

Which of the following proteins uses ATP to maintain membrane asymmetry?

Maintenance of phospholipid asymmetry across leaflets requires energy-driven transport because spontaneous flip-flop faces large kinetic barrier. Phosphatidylserine and phosphatidylethanolamine enriched inner leaflet carry negative curvature and anionic charge recruiting polybasic proteins; their headgroups contain phosphate and serine ethanolamine that cannot traverse hydrocarbon core without passing high energy transition state estimated twenty kilocalories. P4-ATPases termed flippases ATP8A1, ATP8A2, ATP11A, ATP11C hydrolyze ATP cycling through E1 to E2 conformational changes creating water-filled pathway lined by polar residues forming groove accommodating headgroup translocating lipids from outer to inner leaflet against concentration gradient maintaining inner enrichment. Floppases ABC transporters ABCB1, ABCB4 move phosphatidylcholine outward ATP dependent supporting bile secretion, scramblases TMEM16F phospholipid scramblase 1 calcium activated catalyze bidirectional nonselective mixing during platelet activation and apoptosis exposing PS as eat-me and procoagulant signal. Spectrin actin lack lipid transport activity but stabilize bilayer indirectly. Structural studies reveal credit-card like groove accommodating headgroup transport demonstrating molecular mechanism of phospholipid flipping across bilayer.

Ref: Pomorski and Menon, Lipid Flippases and Membrane Asymmetry, Annu Rev Cell Dev Biol 2016.

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