Medic_Summaries (IMS) Topic 4
Membranes, Lipids and Signalling
Compartments: mammalian cells are made up of a series of sub-cellular compartments, such as
mitochondria, Golgi apparatus, nucleus, etc. all surrounded by a membrane (mitochondria have
two membranes). Organelle membranes have different physical and chemical properties (can
separate by CENTRIFUGATION). Vesicles have a bilipid structure with an aqueous centre;
membranes bud off certain organelles and travel to other organelles.
Singer and Nicholson (1972): fluid mosaic model
- The fluid mosaic model describes how lipids in a bilayer form 2D proteins that float
- Some proteins completely cross the bilayer one, or more, times
- Hydrophilic headgroups protrude into the aqueous phase
- Hydrophobic tails interact with each other
- Different lengths of fatty acid tails (FAs) with different numbers of unsaturated C=C bonds
- Cholesterol exists in many animal membranes
- Percentage distribution of different head groups on inner leaflet is different to outer leaflet
Lipid rafts: where average composition of a patch of membrane is different to bulk composition
Glycerophospholipids: derived from glycerol-3-phosphate (glycerol, phosphate group and 2FAs)
- 2FAs are esterified to two hydroxyl groups of glycerol
- Phosphate group forms a diester with the glycerol
- Various FAs are incorporated into phosphoglycerol (R-groups)
Fatty acid tails:
- Even number of C atoms, as two-carbon molecule (acetate) added on to growing FA chain
- No double-bonds = saturated
Headgroups of glycerophospholipids (X=):
- H: phosphatidic acid
- Ethanolamine: phosphatidylethanolamine
- Choline: phosphatidylcholine
- Serine: phosphatidylserine
- Myo-inositol: phosphatidylinositol (intracellular signalling)
- Glycerol: phosphatidylglycerol
- Phosphatidylglycerol: diphosphatidylglycerol
The bilayer:
- The bilayer provides fluidity (as no covalent bonds between lipids)
- Lipids can rotate on their axis/move laterally (lateral diffusion)
- Lipids do not easily flip from one leaflet to another as it is energetically unfavourable
(transverse diffusion (FLIP FLOP))
Phosphatidylcholine translator (ABCB4):
- Progressive familial intrahepatic cholestasis
- Presents in early childhood
- Signs/symptoms: cholestasis, jaundice, failure to thrive
Translocase enzymes: flip phospholipids across the membrane (energy-dependent)
Scramblase enzymes: randomise headgroup/membrane distribution, undo work of translocases
Scramblases are switched on only under special circumstances:
- Platelet activated
- Sperm fertilising an egg
- Apoptosis
1 Adapted from Lectures at the University of Leeds Medical School
,Medic_Summaries (IMS) Topic 4
Exposure of phosphatidylserine: interaction with blood clotting factors on surface of platelet
leads to blood coagulation
Apoptosis: suicide pathway for cells
- ‘FIND ME’ signals attract phagocytes
- Phagocytes use engulfment receptors on their surface to engage ‘EAT ME’ signals on
apoptotic cells
Straight chain carbons (FAs) = SATURATED
Double bonds = UNSATURATED
Membrane fluidity:
- Unsaturated hydrocarbon tails of phospholipids contain C=C double bonds
- Double bonds produce kinks that keep molecules from packing together
- Loose packing of molecules increases membrane fluidity
Frostbite: problem for humans, not deer
- Saturated/unsaturated lipids, together, leave membrane as semifluid at room temperature
- At cold temperatures, membrane solidifies
- Solidification leads to frostbite damage as oxygen cannot diffuse through cell membranes
- Prolonged exposure to frostbite damage leads to cell death
- Reindeer: no frostbite, higher percentage of unsaturated lipids, fluid at lower temperature
Desaturases: four enzymes in mammals that introduce double bonds into FAs
- eg. delta-9-desaturase = double bond at 9oC, FADS1 = delta-6-desaturase
- Diseases associated with FADS1:
- Vitelliform macular dystrophy
- Lung mucoepidermoid carcinoma
- Humans can desaturate FAs at some positions, but not others
- Linolenic acid and linoleic acid (from diet) are essential for FA synthesis
- Omega-3 and -6 FAs help in the maintenance of normal membrane function
Other lipid classes: sphingolipids/sphingomyelin
- Sphingolipids: sphingosine as backbone, not glycerol; FAs attached to sphingosine
- Sphingosine: long chain of carbon atoms
- Sphingomyelin: choline headgroups
Cholesterol: major sterol in mammalian cells
- Rigid
- Compact, fused ring structure
- Aliphatic chain
- Sphingolipids pack closely with cholesterol
Lipid raft: use centrifugation techniques to separate
- Cholesterol-rich
- Sphingolipid-rich
Diseases linked to lipid raft alterations:
- Neuronal: SLO syndrome, Huntington’s, Alzheimer’s, Niemman-Pick type C
- Autoimmune: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA)
Lipid rafts: signalling platforms
- Excess/depletion of lipid raft by reducing/increasing elements leads to signalling platforms
and cellular communication affects
- Membranes form caveolae and invaginate (viruses internalised into cells = endocytosis)
Gangliosides:
- Sugar attached to sphingosine (membrane sphingolipids)
- Abundant in the brain
2 Adapted from Lectures at the University of Leeds Medical School
, Medic_Summaries (IMS) Topic 4
Glycolipids (eg. gangliosides) contain hydrophilic sugar groups on the outer surface of their
plasma membrane. Sugars are added to certain proteins (eg. glycoproteins and gangliosides in
ER). Vesicles bud off ER and travel to Golgi apparatus, where further sugars are added to create a
branched antenna structure. Vesicles bud off Golgi and fuse with the membrane, releasing their
contents. Vesicles and membranes are reinternalised during endocytosis and vesicles fuse with
lysosomes (sugar tree trimmed).
Lysosomes:
- Sites of degradation in cells
- Trim back sugar trees on glycolipids
Amphipathic: cholesterol, phospholipids, glycerolipids (form membranes)
- Storage lipids, triacylglycerols and cholesterol esters do not form membranes
- Lipoproteins are surrounded by a layer of phospholipids
- Lipid storage droplets: triacylglycerols/cholesterol esters deposited in cells
- Adrenal glands: cholesterol ester droplets store cholesterol (steroid hormone production)
- Liver: triacylglycerols and cholesterol esters stored after a meal (lipoproteins time after)
- Hepatosteatosis: liver takes up more lipid than in diet (large lipid droplets in tissue)
Liposomes:
- Simple vesicles that are artificially made
- Found in blood, originating from remains of cells/exosomal particles containing proteins
- Artificial liposomes dyes added to drugs/RNA/DNA as tools for diagnostics and surgery
- Surface manipulation allows for specific targeting
Membrane proteins and carbohydrates:
- Alzheimer’s disease: most common cause of dementia
- Dementia: umbrella term for serious deterioration in mental functions (memory, language,
orientation and judgement)
- Nerve cells in the brain die and connections between nerve cells degenerate
- Loss of memory (hippocampus) is the first symptoms
Alzheimer’s disease (AD):
- Clinical features of AD:
- Amnesia: recent memories initially affected
- Aphasia: language problems
- Agnosia: difficulty recognising and naming objects
- Autoprosopagnosia: failure to recognise own face
- Apraxia: difficulties in complex tasks
- Visuospatial difficulties
- Functional impairment: often most impact on individual
- Mood disorders
- Psychosis: delusions, hallucinations
- Personality change: living bereavement
- No drugs currently cure AD
- Brain atrophies (shrinks) as nerve cells die
- PET scan shows that glucose is poorly metabolised
- Dementia care is more than cancer, stroke and heart disease together
- Neurones malfunction and die (chemical signalling between cells goes wrong)
- We do NOT yet know why this happens
- Pathological brain lesions (senile plaques) usually present = amyloid beta-peptide (AB-P)
- AB-P is proteolytically cleaved from membrane-bound amyloid precursor protein (APP)
Current drugs:
- Cholinesterase inhibitors: aricept (donepezil), exelon (rivastigmaine), reminyl (dantamine)
- NMDA receptor antagonist: ebixa (memantine)
- Anti-psychotic drugs
- These do NOT cures, they just relieve some of the symptoms
3 Adapted from Lectures at the University of Leeds Medical School
Membranes, Lipids and Signalling
Compartments: mammalian cells are made up of a series of sub-cellular compartments, such as
mitochondria, Golgi apparatus, nucleus, etc. all surrounded by a membrane (mitochondria have
two membranes). Organelle membranes have different physical and chemical properties (can
separate by CENTRIFUGATION). Vesicles have a bilipid structure with an aqueous centre;
membranes bud off certain organelles and travel to other organelles.
Singer and Nicholson (1972): fluid mosaic model
- The fluid mosaic model describes how lipids in a bilayer form 2D proteins that float
- Some proteins completely cross the bilayer one, or more, times
- Hydrophilic headgroups protrude into the aqueous phase
- Hydrophobic tails interact with each other
- Different lengths of fatty acid tails (FAs) with different numbers of unsaturated C=C bonds
- Cholesterol exists in many animal membranes
- Percentage distribution of different head groups on inner leaflet is different to outer leaflet
Lipid rafts: where average composition of a patch of membrane is different to bulk composition
Glycerophospholipids: derived from glycerol-3-phosphate (glycerol, phosphate group and 2FAs)
- 2FAs are esterified to two hydroxyl groups of glycerol
- Phosphate group forms a diester with the glycerol
- Various FAs are incorporated into phosphoglycerol (R-groups)
Fatty acid tails:
- Even number of C atoms, as two-carbon molecule (acetate) added on to growing FA chain
- No double-bonds = saturated
Headgroups of glycerophospholipids (X=):
- H: phosphatidic acid
- Ethanolamine: phosphatidylethanolamine
- Choline: phosphatidylcholine
- Serine: phosphatidylserine
- Myo-inositol: phosphatidylinositol (intracellular signalling)
- Glycerol: phosphatidylglycerol
- Phosphatidylglycerol: diphosphatidylglycerol
The bilayer:
- The bilayer provides fluidity (as no covalent bonds between lipids)
- Lipids can rotate on their axis/move laterally (lateral diffusion)
- Lipids do not easily flip from one leaflet to another as it is energetically unfavourable
(transverse diffusion (FLIP FLOP))
Phosphatidylcholine translator (ABCB4):
- Progressive familial intrahepatic cholestasis
- Presents in early childhood
- Signs/symptoms: cholestasis, jaundice, failure to thrive
Translocase enzymes: flip phospholipids across the membrane (energy-dependent)
Scramblase enzymes: randomise headgroup/membrane distribution, undo work of translocases
Scramblases are switched on only under special circumstances:
- Platelet activated
- Sperm fertilising an egg
- Apoptosis
1 Adapted from Lectures at the University of Leeds Medical School
,Medic_Summaries (IMS) Topic 4
Exposure of phosphatidylserine: interaction with blood clotting factors on surface of platelet
leads to blood coagulation
Apoptosis: suicide pathway for cells
- ‘FIND ME’ signals attract phagocytes
- Phagocytes use engulfment receptors on their surface to engage ‘EAT ME’ signals on
apoptotic cells
Straight chain carbons (FAs) = SATURATED
Double bonds = UNSATURATED
Membrane fluidity:
- Unsaturated hydrocarbon tails of phospholipids contain C=C double bonds
- Double bonds produce kinks that keep molecules from packing together
- Loose packing of molecules increases membrane fluidity
Frostbite: problem for humans, not deer
- Saturated/unsaturated lipids, together, leave membrane as semifluid at room temperature
- At cold temperatures, membrane solidifies
- Solidification leads to frostbite damage as oxygen cannot diffuse through cell membranes
- Prolonged exposure to frostbite damage leads to cell death
- Reindeer: no frostbite, higher percentage of unsaturated lipids, fluid at lower temperature
Desaturases: four enzymes in mammals that introduce double bonds into FAs
- eg. delta-9-desaturase = double bond at 9oC, FADS1 = delta-6-desaturase
- Diseases associated with FADS1:
- Vitelliform macular dystrophy
- Lung mucoepidermoid carcinoma
- Humans can desaturate FAs at some positions, but not others
- Linolenic acid and linoleic acid (from diet) are essential for FA synthesis
- Omega-3 and -6 FAs help in the maintenance of normal membrane function
Other lipid classes: sphingolipids/sphingomyelin
- Sphingolipids: sphingosine as backbone, not glycerol; FAs attached to sphingosine
- Sphingosine: long chain of carbon atoms
- Sphingomyelin: choline headgroups
Cholesterol: major sterol in mammalian cells
- Rigid
- Compact, fused ring structure
- Aliphatic chain
- Sphingolipids pack closely with cholesterol
Lipid raft: use centrifugation techniques to separate
- Cholesterol-rich
- Sphingolipid-rich
Diseases linked to lipid raft alterations:
- Neuronal: SLO syndrome, Huntington’s, Alzheimer’s, Niemman-Pick type C
- Autoimmune: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA)
Lipid rafts: signalling platforms
- Excess/depletion of lipid raft by reducing/increasing elements leads to signalling platforms
and cellular communication affects
- Membranes form caveolae and invaginate (viruses internalised into cells = endocytosis)
Gangliosides:
- Sugar attached to sphingosine (membrane sphingolipids)
- Abundant in the brain
2 Adapted from Lectures at the University of Leeds Medical School
, Medic_Summaries (IMS) Topic 4
Glycolipids (eg. gangliosides) contain hydrophilic sugar groups on the outer surface of their
plasma membrane. Sugars are added to certain proteins (eg. glycoproteins and gangliosides in
ER). Vesicles bud off ER and travel to Golgi apparatus, where further sugars are added to create a
branched antenna structure. Vesicles bud off Golgi and fuse with the membrane, releasing their
contents. Vesicles and membranes are reinternalised during endocytosis and vesicles fuse with
lysosomes (sugar tree trimmed).
Lysosomes:
- Sites of degradation in cells
- Trim back sugar trees on glycolipids
Amphipathic: cholesterol, phospholipids, glycerolipids (form membranes)
- Storage lipids, triacylglycerols and cholesterol esters do not form membranes
- Lipoproteins are surrounded by a layer of phospholipids
- Lipid storage droplets: triacylglycerols/cholesterol esters deposited in cells
- Adrenal glands: cholesterol ester droplets store cholesterol (steroid hormone production)
- Liver: triacylglycerols and cholesterol esters stored after a meal (lipoproteins time after)
- Hepatosteatosis: liver takes up more lipid than in diet (large lipid droplets in tissue)
Liposomes:
- Simple vesicles that are artificially made
- Found in blood, originating from remains of cells/exosomal particles containing proteins
- Artificial liposomes dyes added to drugs/RNA/DNA as tools for diagnostics and surgery
- Surface manipulation allows for specific targeting
Membrane proteins and carbohydrates:
- Alzheimer’s disease: most common cause of dementia
- Dementia: umbrella term for serious deterioration in mental functions (memory, language,
orientation and judgement)
- Nerve cells in the brain die and connections between nerve cells degenerate
- Loss of memory (hippocampus) is the first symptoms
Alzheimer’s disease (AD):
- Clinical features of AD:
- Amnesia: recent memories initially affected
- Aphasia: language problems
- Agnosia: difficulty recognising and naming objects
- Autoprosopagnosia: failure to recognise own face
- Apraxia: difficulties in complex tasks
- Visuospatial difficulties
- Functional impairment: often most impact on individual
- Mood disorders
- Psychosis: delusions, hallucinations
- Personality change: living bereavement
- No drugs currently cure AD
- Brain atrophies (shrinks) as nerve cells die
- PET scan shows that glucose is poorly metabolised
- Dementia care is more than cancer, stroke and heart disease together
- Neurones malfunction and die (chemical signalling between cells goes wrong)
- We do NOT yet know why this happens
- Pathological brain lesions (senile plaques) usually present = amyloid beta-peptide (AB-P)
- AB-P is proteolytically cleaved from membrane-bound amyloid precursor protein (APP)
Current drugs:
- Cholinesterase inhibitors: aricept (donepezil), exelon (rivastigmaine), reminyl (dantamine)
- NMDA receptor antagonist: ebixa (memantine)
- Anti-psychotic drugs
- These do NOT cures, they just relieve some of the symptoms
3 Adapted from Lectures at the University of Leeds Medical School
