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MBB266 > Williamson (Biological functions of membranes) > Flashcards

Williamson (Biological functions of membranes) Flashcards

1
Q

What are the functions of membranes from an evolutionary perspective?

A
  • arose as barrier between controlled env of inside and outside (stops content leaking out and random chemicals from coming in)
  • permit and reg transport of nutrients (and waste) = CHANNELS
  • dev ability to do against conc grad = PUMPS
  • all cells do this, “tacked on” to original role of barrier
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2
Q

What are the later developments in the functions of membranes?

A
  • conversion of membrane pot to energy (most cells)
  • cellular recognition (euks and proks, but differently)
  • signalling from outside to inside (all cells but no universal system)
  • movement of molecules w/in euk cell in vesicles
  • compartmentalisation (only euks)
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3
Q

How do cell sizes vary?

A
  • E. Coli ≈ 2μm x 1μm
  • epithelial cell ≈ 10x bigger each way
  • fibroblast ≈ 4x larger width and breadth
  • nerve axon = up to 500,000x longer
  • vol of euk cell ≈1000x greater than prok, so vital need to compartmentalise and direct molecules appropriately
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4
Q

Where are almost all important functions w/in euk cell contained?

A
  • membrane bound vesicles
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5
Q

How does internal membranes SA compare to external?

A
  • internal SA 10x longer than external
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6
Q

What are membranes made up of?

A
  • lipids
  • hydrophobic proteins (prod fluid mosaic structure
  • integral membrane protein
  • peripheral membrane proteins
  • lipid anchored proteins
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7
Q

How do lipids aggregate?

A
  • spontaneously in water

- in lab can aggregate into many diff structures (bilayer, liposome, vesicle) but only into bilayers in cells

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8
Q

How can lateral mobility of proteins be detected?

A
  • FRAP (fluorescence recovery after photobleaching)
  • membrane proteins labelled w/ fluorescent reagent
  • bleach w/ laser, resulted in bleached area
  • membrane proteins diffuse, resulting in fluorescence recovery
  • doesn’t fully recover, ∴ not totally random lipid distribution
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9
Q

What does AFM (atomic force microscopy) show?

A
  • shows height of diff components and proteins embedded in membrane sticking up above lipid bilayer
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10
Q

What is the big problem w/ the fluid mosaic model?

A
  • concs on protein and assumes lipids more or less same

- they aren’t (don’t all completely diffuse freely in membrane)

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11
Q

What are the diff types of membrane lipids?

A
  • main are phospholipids
  • sphingolipids = contain NH instead of O and often trans double bonds instead of cis bonds found in phospholipids
  • sterols (eg. cholesterol)
  • sphingomyelins = mainly sat
  • phosphatidylcholine (PC) = mainly unsat, so lipids in PC layers less linear and more disordered
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12
Q

How does lipid composition affect membrane fluidity?

A
  • cis double bond forces chain to go off at angle
  • trans can fit w/in linear extended chain
  • ∴ bilayers containing cis bonds fairly disordered (fluid phase)
  • bilayers w/ trans bonds more ordered (gel phase)
  • cells normally want membranes to be fluid to allow movement w/in bilayer
  • ∴ PC layers tend to be thinner as less ordered
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13
Q

Can bilayers change between phases?

A
  • any real or artificial bilayer can be induced to change between phases by heating (gel –> fluid)
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14
Q

How does cholesterol affect membrane fluidity?

A
  • at v high conc in some membranes (euks, esp mammals)
  • flat so packs against other flat (trans) lipids and makes them even flatter and ∴ longer
  • implying real biological membranes have idiff thicknesses depending on composition
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15
Q

Why are diff lipids diff shapes?

A
  • so cells can control shape
  • eg. PE headgroup smaller than lipid tail so makes bilayer curved
  • PC basically cylindrical so packs well into flat bilayers
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16
Q

How can cells vary the curvature of membrane?

A
  • lipid composition
  • membrane protein oligomerisation
  • cytoskeleton (cytoskeletal proteins push/pull membrane about)
  • scaffolding = indirect (not directly attached, direct -ve (inside membrane) or direct +ve (outside membrane)
  • amphipathic helix insertion
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17
Q

How do lipid concs vary between diff membranes?

A
  • vary a lot
  • ER, golgi and plasma membrane diff (pm has more cholesterol)
  • carefully controlled by cell to give them diff properties
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18
Q

How does lipid distribution vary between 2 leaflets of membrane?

A
  • sphingomyelin and PC mainly in outside (≈3/4)

- phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol (95%) mainly in inside

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19
Q

Are proteins in the membrane in 1 orientation?

A
  • 100% in 1 orientation
  • GPI anchored all outside
  • lipid anchored all inside
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20
Q

What is the role of anchors in membranes?

A
  • can be added or removed (and changed)
  • anchors direct to diff membranes and diff parts of cells
  • can direct proteins reversibly
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21
Q

What is flippase?

A
  • ATP-dep enzyme

- flips lipids between bilayer leaflets (not spontaneous)

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22
Q

Why does phase separation of diff lipid components occur?

A
  • to vary lipid composition
  • creates diff regions w/in membrane
  • thicker and more rigid regions richer in cholesterol and sphingolipids called membrane rafts
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23
Q

What are membrane rafts?

A
  • rigid blocks diff from rest of membrane
24
Q

How do proteins segregate into diff regions?

A
  • proteins w/ longer transmembrane helices go into membrane rafts
  • proteins w/ GPI anchors go into membrane rafts
  • proteins w/ palmitoyl anchors go into membrane rafts
  • proteins w/ prenyl anchors prefer not to be in membrane rafts
25
Q

How are membrane rafts formed?

A
  • controlled by cell and important mechanism for alt location of membrane proteins
  • eg.
  • -> bringing signalling systems together
  • -> organising start of endocytosis
  • -> T cell activation
26
Q

What does AFM imaging of GPI anchored proteins in rafts show?

A
  • model membrane made of dioleoylphosphatidylcholine
  • also contains sphingomyelin, which collects into patches (these are thicker layers)
  • contain GPI anchored protein, almost entirely found in rafts
27
Q

How are rafts a good way to bring proteins together or to keep them apart?

A
  • small rafts become larger rafts w/ stimulation –> so some brought close together and some further apart
  • attachment of GPI anchor, prenylation etc. is covalent mod and can be easily alt
  • ∴ many proteins can be easily moved in and out of rafts
  • opp true = if proteins don’t want to be in raft, add tags to separate them
28
Q

Where are lipid rafts thought to have important functions?

A
  • signalling

- membrane trafficking

29
Q

How do lipid rafts move proteins around?

A
  • use membranes to do it
  • proteins tagged w/ signal seq to direct them to right place
  • typically proteins tagged, but so are membrane ‘parcels’ that contain them
  • lots of recycling to make sure proteins end up where meant to be
  • all tightly reg
  • most tagging done by proteins, but lipid composition also reg targeting
  • almost all movement along MT tracks
30
Q

What is the process of ligand-mediated endocytosis?

A
  • brought about by membrane rafts
  • start w/ flat membrane, ligand binds to receptor and activates it
  • formation of membrane raft
  • proteins (caveolin) bind to membrane raft, insert halfway into membrane and make it curved
  • caveolin recruits more proteins (cavin, clathrin), makes coat around caveolae (invagination)
  • caveolae pinched off at top and move into cell
31
Q

What is patch clamping and what did it show?

A
  • attach v sensitive electrode to patch of membrane and measure current across membrane
  • pipette filled w/ buffer and either applying small amount of suction (to get whole cell to measure all receptors
    • -> by pulling (inside out to measure channels that open w/ internal binding
    • -> or by suction then pulling (to outside out = most useful)
  • found 2 ‘excited’ levels –> 1st level = 1 channel open and 2nd level = 2 open
  • excited levels at fixed positions, shows all channels have same current when open
  • opening and closing essentially random (indiv channels open for random amount of time) –> av opening and closing rates specific to channel
32
Q

What are the types of ion channels present in axons?

A
  • VG Na+ channel
  • VG K+ channel
  • Na+/K+ pump
  • ‘resting’ K+ channel
33
Q

What is the role of VG Na+ channels?

A
  • channel starts to open at -40mV
  • max ion flow when pot is 0 or +ve
  • has ‘plug’ which closes after channel open ≈1ms, plug detaches few ms after membrane pot returned to normal
    1) closed Na+ channel - initial depolarisation, movement of voltage sensing α helices, opening of channel (<0.1ms)
    2) open Na+ channel - return of voltage sensing α helices to resting position, inactivation of channel (0.5-1ms)
    3) inactive Na+ channel (refractory period)
    4) repolarisation of membrane, displacement of channel - inactivating segment and closure of gate (slow, several ms)
34
Q

What is the role of VG K+ channels?

A
  • similar to Na+ channels, closed w/ -ve pot and open as pot gets less -ve
  • main diff is opening/closer slower
  • ∴ sometimes called ‘delayed’ K+ channel
  • also has plug
35
Q

What is the role of Na+/K+ pump?

A
  • ATP dep
  • constantly pumps 3Na+ out and 2K+ in
  • maintains Na+/K+ concs inside cell that are v diff from extracellular concs
36
Q

What is the role of resting K+ channels, and why is this important?

A
  • ‘resting’ as open even when cell at rest
  • allow K+ to leak all the time and gives cell membrane its -ve pot
    WHY?
  • if membrane w/ no channels open and physiological K+ grad across membrane, K+ will rush out to equalise concs when K+ channels open
  • leaving -ve charge inside and create +ve charge outside
  • w/in short distance either side of membrane, K+ concs equal, held by charge separation across membrane
  • at this point have stable situation, w/ -ve membrane pot
37
Q

How do nerve impulses (action pots) work?

A
  • neurons form network
  • motor neurons have axons pointing from spinal cord to muscle
  • sensory neurons point from tissue to spinal cord
  • nerve impulse is transient change in membrane pot, “all or nothing”
  • stronger signal obtained by more action pots
  • can’t get closer than 4ms (refractory periods)
38
Q

What happens during transmission of an action potential?

A
  • at synapses, signal transmitted from 1 cell to next by neurotransmitters
  • neurotransmitters stored in vesicles at end of axon
  • arrival of AP triggers exocytosis of vesicle
  • diffuse across synapse and bind to receptors
  • opening of channel in postsynaptic membrane which activates signal
39
Q

How do neural junctions differ from NMJs?

A
  • at NMJ 1 AP = 1 transmitted signal, all that needs to happen
  • at neural more complicated ‘logic gate’
      • signal can prod +ve or -ve response, which add up
    • -> AP only started in 2nd neuron when net voltage at axon hillock reaches certain threshold (input from many neurons)
40
Q

How does K+/Na+ ration determine resting pot in all cells?

A
  • -60mV pot across resting state cell membrane (inside more -ve)
  • true in almost all human cells
  • comes mainly from K+ flow out through resting K+ channels
  • continually need to pump K+ in and Na+ out (K+/Na+ pump)
  • ≈25% total ATP consumption used to power this pump
41
Q

What is useful consequence of refractory period?

A
  • action pot can only go forwards
42
Q

How is an AP transmitted?

A
  • AP moving along cell depolarises membrane
  • enough to raise pot above -40mV which opens Na+ channels
  • Na+ influx (large conc grad)
  • makes pot more +ve and leads to more channels opening, +ve feedback and v rapidly all Na+ channels open
  • Na+ influx and pot up to ≈35mV
  • after 1ms ish, plug in Na+ channels closes all channels
  • now at peak of AP
  • delayed K+ channels start to open due to +ve pot
  • allows K+ efflux and makes pot -ve again
  • K+ flow enough to hyperpolarise membrane briefly
  • plug in Na+ channel stops it opening for several ms (refractory period)
43
Q

What effect do APs have on membrane and overall Na+/K+ concs?

A
  • large effect on membrane

- little effect on overall concs (≈1% moved per μm2 of membrane

44
Q

Do APs change in size as they travel down axon?

A
  • same size
45
Q

How can toxins affect APs?

A
  • many work by blocking diff aspects

- eg. Japanese puffer fish poisonous due to tetrodotoxin which blocks VG Na+ channels

46
Q

What is the role of myelin sheaths?

A
  • APs travel at ≈1m/s
  • allow up to 100x
  • has gaps approx 1μm long every 100μm
  • membrane only contacts extracellular fluid at these nodes
  • allows pot to jump from 1 node to next
47
Q

What causes MS?

A
  • loss of myelin in some areas of brain and spinal cord

- eventually nervous system shuts down

48
Q

Why is signalling vital for all cells?

A
  • response to hormones, GFs, infection, neural synapses, bacterial response to env
49
Q

How does signalling vary?

A
  • ranges from v short term (vision, pain) to v long term (cellular differentiation)
  • may need turning off, others constitutively expressed (sex hormones)
50
Q

What are the major pathways for signals to enter the cell?

A
  • receptor linked kinases
  • G protein coupled receptors (GPCRs)
  • ion channels
51
Q

Which pathways for signals entering the cell use G proteins and what role do they play?

A
  • receptor kinases and GPCRs
  • eg. Ras
  • turned on by dissociation of GDP and binding GTP, using GEFs (guanine exchange factors)
  • turned off by hydrolysing GTP to GDP (simpler process), using GAPs (GTPase activating proteins)
52
Q

How do receptor linked kinases work?

A
  • hormone binds and receptor dimerises
  • autophosphorylation
  • phosphorylation of 1 kinase domain by other fixes position of activation loop, allowing it to bind substrate correctly
  • phosphorylated receptor now the intracellular on signal –> acts as binding site for modular adaptor proteins
  • SH3 domain recognises polyproline helices
  • SH2 domain recognises phospotyrosines (specific SH2 for each receptor)
  • plug together to bring GEF to cell surface
53
Q

How does Ras perform its function now that it’s an active G protein?

A
  • main function to activate kinase called raf
  • raf at top of kinase cascade (seq of kinase that phosphorylate each other and amplify signal at each step
  • MAPKKK –> MAPKK –> MAPK
  • MAPK moves into nucleus and phosphorylates several TFs
  • complicated but allows mod of signal in diff ways
54
Q

Are GPCRs common drug targets?

A
  • largest group of proteins used as drug targets

- used by half of current drugs

55
Q

How do GPCRs work?

A
  • 7 TM helices
  • intracellular loops bind to heterotrimeric G protein
  • ligand binds well w/in membrane
  • heterotrimeric (3 diff subunits) –> β and γ always paired
  • receptor bound GPCR acts as GEF and turns on signal
  • Gα-GTP now active and moves along membrane looking for something to activate
  • adenylyl cyclase common target
  • converts ATP to cAMP when bound to Gα-GTP
  • cAMP acts as 2nd messenger elsewhere in cell
  • bound GTP rapidly hydrolysed to GDP by Gα, turning off signal (Gα is its own GAP)
56
Q

What are some other targets of activated Gα?

A
  • some G proteins indirectly open or close ion channels
  • smell and vision work in this way
  • binding of odorants to specific receptors activates Gα, activates adenylyl cyclase
  • cAMP opens Na+ channels, initiating neuron depolarisation
  • light leads to alteration in conc of cGMP (works in similar way)
  • important class of GPCRs work by Gα activating phospholipase C (PLC)
57
Q

How do ion channels work? (pathway for signals to enter cell?

A
  • ligand gated channels so need to be v responsive to ligand conc
  • may have multiple subunits (often 5)
  • ACh receptor works by simultaneous rotation of each subunit to open up channel

MBB266 (7 decks)

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