biochemistry of membrane lipids

8/17/2019 Biochemistry of Membrane Lipids

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Bhaskar Ganguly

Ph.D. , M.V.Sc. , B.V.Sc. A.H.


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•

Overton {1890s}:Lipids are present on cell surfaces; cell coats are probably mixtures

of cholesterol & lecithin

•

Langmuir {1900s}:Phospholipid monolayer

• Gorter & Grendel {1925}:Lipid Bilayer


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•

Davson & Danielli {1935}:Biological membranes consist of lipid bilayers coated on both sides

by thin sheets of proteins

• Robertson {1960}:

All cellular membranes share a common underlying structure viz.

Unit Membrane


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•

Singer & Nicolson {1972}:Biological membranes consist of a mosaic of proteins in a lipid

bilayer; ‘The Fluid-Mosaic Model’


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• Behavior of lipid matrix depends on the properties ofindividual lipid components

• Lipid matrix interacts with proteins and influences activity ofthe proteins

• Depending on duration of interactions, lipids are classified as

Restricted lipids: long residence time, slow exchange withsurrounding lipids

Interfacial lipids: form coat or ring around the circumferenceof proteins, exchange rapidly with surrounding lipids

• Restricted and Interfacial lipids may be necessary for proteinfunction


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• Form structural and environmental framework for cell function

• Phosphatidylcholine (PC), phosphatidylserine (PS) &phosphatidylinositol (PI): provide hydrated or chargedmembrane surfaces, allowing water/ ions to bind

• Phosphatidylethanolamine (PE): hydrophobic, promotes

surface interactions without protein-protein interactions,promotes formation of non-bilayer structures; necessary formembrane fusion

• Asymmetrical distribution between inner and outer leaflets

Outer leaflet: rich in PC & sphingomyelinInner leaflet: rich in PE & PS

• Asymmetrical distribution is achieved & maintained by ATP-dependent Aminophospholipid Translocase; translocates PE &

PS between leaflets


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Differential distribution of lipids in leaflets


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Per cent distribution of phospholipids in erythrocyte membrane

Role of translocases/ flippases in maintaining membrane asymmetry


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• Reduces freedom of movement of phospholipids, rigidifyingeffect on membrane viz. ‘Condensing effect’

•

Non-uniform distribution in different cell membranes• Decreases fluidity at high temperatures; increases fluidity at

low temperatures

• Decreases permeability to ions & small polar molecules


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At low temperatures, cholesterol disallows close packing of hydrocarbon chains; at high

temperatures, the rigid molecule restricts freedom of the acyl chains


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• A state of change achieved by the motions of individualmembrane components & their interrelationships in non-repeating units of the membrane

• Asymmetric distribution of different lipids adds anotherdimension to Membrane Dynamics

• Re-distribution (lateral &/ or transverse) influences membraneproperties, and allows differential regulation of membraneproteins

•Biological case studies:

PLATELETS, & PHOTORECEPTORS


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(%) lipids in plasma membrane

PC

PE

PI

PS

Sphingomyelin

• PC & Sphingomyelin in

outer leaflet; PE & PS ininner leaflet

• Cholesterol : Phospholipid≈ 0.50

• Platelets cannot synthesizecholesterol; derived frommegakaryocyte progenitor

• Membrane cholesterol concentration represents plasmacholesterol concentration

• Membrane cholesterol is also acquired from plasmalipoproteins


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• Upon stimulus for aggregation, asymmetry of phospholipiddistribution is lost

• PE is rapidly translocated from inner to outer leaflet

• Aminophospholipid translocase is not inhibited; instead,‘Scramblase’ is involved (induced by high intracellular Ca++)

•

Cholesterol translocates from outer to inner leaflet;thermodynamic exclusion of cholesterol due to unfavorableentropy of co-existence with PE

• Higher cholesterol results in stronger response to stimulus

• High membrane cholesterol platelets are more sensitive toepinephrine, ADP, collagen & thromboxane A2

• Cholesterol enrichment increases signaling events viz. releaseof arachidonic acid, increased adrenergic & thrombin

receptors, and higher Ca++ & inositol phosphate levels


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• Cholesterol behaves both as a restricted and interfacial lipid

•Platelet stimulation increases rigidity & decrease fluidity

• Activation of platelets alters platelet membrane to create acatalytic site for conversion of factor X to factor X-a, and ofprothrombin to thrombin, leading to fibrinogen formation

• Creation of catalytic site requires surfacing of PS from theinner leaflet


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• Biochemical events initiating the impulse occur in membranoussacs called ‘disks’ in the ROS

• New disks form from the ROS plasma membrane; old disks

displaced apically are shed off & phagocytosed by retinalepithelium (≈ 10 days)

R o d O u t e r S e g m e n t

( R O

S )

Plasma

Membrane

Disk


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• Disks & Plasma membranes differin lipid composition

• Plasma membrane: richer incholesterol & squalene (sterolprecursor), PE:PC = 0.16,docosahexaenoic acid (DHA) ~5 %

• Disks: PE:PC = 0.92, DHA ~ 35 %

11-cis retinal ↓ all trans retinal

Rhodopsin ↓Metarhodopsin I ↓Metarhodopsin II

Metarhodopsin II ↓ Transducin ↓

cGMP dependentPhosphodiesterase (PDEase)

• Basal disk ~ 30 mol% cholesterol, apical disk ~ 5 mol%; samemechanism as platelets (exclusion from PE-rich disk membrane)

•Cholesterol influences rhodopsin function; ↑ cholesterol inhibitsactivation of PDEase by rhodopsin

• Conversion of Metarhodopsin I to larger Metarhodopsin II requires kinking of unsaturated acyl chains; cholesterol resists

these free volume changes


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• Cholesterol also interacts directly with rhodopsin

• DHA influences regeneration of rhodopsin

• DHA can contribute as six cis- bonds; cis- bonds increasekinking within membrane bilayer thereby increasing free

volume • Rhodopsin is maintained in a relatively inactive state in plasma

membrane; ↑ cholesterol (= inhibition of activation), ↓ DHA (=slow regeneration), i.e., ↑ Cholesterol/DHA favors inactivity

• In disk membrane, ↓ Cholesterol/DHA favors rapid activationand regeneration necessary for proper vision


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