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Membranes - Coggle Diagram

- - - - Phosphatidylcholine has a head group of choline esterified to the negatively charged phospahte
      - phosphoinositides have an OH containing sugar derivative of inositol which has been further modified with phosphates
      - Lysophospholipids are formed when phospholipases act on phosphoglycerides and lack one of the 2 acyl chains
      - plasmalogens contain one fatty acyl chain attaches to carbon 2 of glycerol by an ester linkage and one long hydrocarbon chain attached to carbon 1 of glycerol by an ether (the stability of ether has unrecognised significance
  - - - only from artificial desaturation
  - - - ceramide is just H
      - sphingomyelin has phosphocholine
      - glycolipids have polar heads that are sugars which are not linked to the tails via a phosphate group so are not phospholipids (glucosylcerebroside contains a single glucose unit but gangliosides have one or two branched oligosaccharides containing sialic acid groups attached to sphingosine
  - - - has a hydroxyl substitute on one ring, so interacts with water
      - has lipid ordering effect that increases thickness
      - it is a precursor for several bioactive molecules like bile acids to emulsify dietary fats, steroid hormones, vitamin D
  - - - stands for fluorescence recovery after photobleaching adn quantifies lateral movement
      - phospholipids containing fluorescent substituent and protein have specific antigen binding tagged with fluorescent dye
      - Process
        
        cells labelled with fluorescent reagent or protein can be tagged with GFP
        
        lazer light is focused on to small area of surface which bleaches the reagent or GFP to reduce fluorescence in illuminated area
        
        over time there is an increase in fluorescence of the bleached area as unbleached molecules diffuse into it
        
        the extent of recovery of fluorescence in the bleached patch is proportional to the fraction of labelled molecules that are mobile in the membrane
      - results show that all phospholipids are freely mobile over distance of 0.5um but most cannot diffuse further, also show that they cannot diffuse from a lipid rich region to an adjacent one, and that lateral diffusion is ten times faster in pure phospholipid bilayers than plasma membranes (suggesing that lipids may be tightly but not irreversibly bound to certain integral proteins)
  - - - kinks in cis-unsaturated fatty acyl chains results in forming less stable van der Waal interactions so more fluid bilayers
      - Cholesterol restricts random movement of phospholipid head groups at outer surface of leaflets, but effect on long tails depends on its concentration: at normal levels the sterol ring tends to immobilise those lipids and decrease fluidity; but lower concentrations the sterol ring separates and disperses phospholipids tails causing inner regions to becomes slightly more fluid
      - van der Waal interactions and hydrophobic effect cause nonpolar tails of phospholipids to aggregate, and so shorter fatty acyl chains have fewer van der Waal interactions adn form more fluid bilayers
      - membrane fluidity is decreased by sphingolipids and cholesterol but increased by phosphoglycerides
    - - argued that short transmembrane segments of certain Golgi glycosyltransferases are an adaptation to the lipid composition and contribute to enzyme retention
      - studies found that sphingomyelin associates in gel like and thicker bilayer than phosphoglycerides
      - cholesterol decrease fluidity and increase thickness, but because sphingomyelin tails are optimally stabilised, the addition of cholesterol causes no change
    - - Bilayers composed of cylindrical lipids are relatively flat whereas those containing large number of cone shaped lipids form curved bilayers
      - several proteins, like reticulons, bind to the surface of a phospholipid bilayer and cause the membrane to curve, this is important in formation of transport vesicles that bud from a donor membrane
    - - Human erythrocytes and MDCK cells have sphingomyelin and PC in exoplasmic leaflet (less fluid), and PE, PS and PI in cytosolic leaflet (more fluid). PI and PS carry net negative charge so stretcj of amino acids on cytosolic face is positively charged (the "inside positive" rule)
      - cholesterol is relatively evenly distributed in both leaflets
      - abundances can be determined experimentally using phospholipases since they cleave off heads of only exoplasmic lipids as cannot penetrate plasma membrane
      - Sphingomyelin is synthesised on luminal face of Golgi that becomes exoplasmic face of plasma membrane, phosphoglycerdes are synthesised on cytosolic face of ER so cytosolic face of plasma membrane, but there is PC in exoplasmic leaflet likely from ATP powered flippases
      - Cell signalling
        
        All the phosphorylated forms of PI are on cytosolic leaflet. stimulation of certain receptors by ligands causes activation of PLC which can hydrolyses the bond within PI connecting phosphoinositols and diacylglycerol. the water soluble phosphoinositols and membrane embedded diacylglycerol are involved in signalling
        
        PS is abundant on cytosolic face and in initial stages of platelet stimulation by serum PS is briefly translocated to exoplasmic face where it activates enzymes in blood clotting
        
        when a cell dies lipid assymetry is lost, so PS is found more on exoplasmic leaflet (detected experimentally by labelled version of annexin V) and the increased PS is recognised by phagocytic cells
- - - - the amino acid side chains protrude outward and interact with hydrocarbon core
      - contain one or more alpha helices which are embedded by hydrophobic and van der waals interactions of the hydrophobic side chains inthe domain with specific lignads
      - a single alpha helix is enough to incorporate but many proteins have multiple, they are also perpendicular to the plane of the membrane
    - - Glycophorin A
        
        single pass transmembrane protein as only contains one membrane spanning a helix
        
        23 residue membrane spanning helix composed of hydrophobic amino acid side chains that interact with fatty acyl chains
        
        it typically forms dimers- the helix will associate with corresponding helix of another glycophorin to form a coiled structure
        
        the extracellular domain is heavily glycosylated with carbohydrate chains attached to Ser, Thr, and Asp
      - G protein coupled cell surface receptors
        
        bacteriorhodopsin is in this family of multipass transmembrane proteins
        
        absorption of light by retinal group covalently attached to the protein causes conformational change in protein causing pumping of protons into extracellular space
        
        This creates a gradient used to synthesise ATP
      - Aquaporins
        
        This is a large family of highly conserved proteins that transport water, glycerol and other hydrophilic molecules
        
        they are a tetramer of 4 identical subunits, each with sex membrane-spanning a helices ( some transverse membrane at oblique angles)
        
        Glpf is an aquaporin with one long transmembrane helix with a bend in the middle and there are 2 a helices that penetrate only halfway through (the N termini face each other), these short helices i naquaporins form part of the glycerol/water selective pore in the middle of each subunit
        
        Aquaporin 0 is the most abundant in fibre cells, like others it is a tetramer of identical subunits, the protein surface is not covered by a set of uniform binding sites but rather fatty acyl chains that pack tightly against the irregular hydrophobic outer surface (the lipids are annular phospholipids as they form a tight ring of lipids), some fatty acyl chains are in trans conformation but some are kinked to interact with bulky hydrophilic side chains
      - T antigen receptors
        
        It is composed of 4 separate dimers, the interactions are driven by charge-charge interactions between a helices at appropriate depth into hydrocarbon core of bilayer
        
        the electrostatic attractio of positive and negative charges on each dimer helps identification and so aid in assembly
        
        (info on subunits in figure 10-17 caption)
      - Porins
        
        They are a class of trimeric transmembrane proteins through which small water soluble molecules can cross the membrane
        
        they are found in gram negative bacteria and in outer membrane of organelles; they provide channels for small molecules
        
        teh amino acid sequence contains no long hydrophic segment domains but rather the entire oter surface of the fully folded porin displays it hydrophobic character to the hydrocarbon core of the lipid bilayer
        
        In each subunit, 16 B strands form a sheet that twists into a barrel shaped structure with a pore in the centre
        
        A porin has a hydrophobic interior and hydrophobic interior- the hydrophobic band interacts with the fatty acyl groups of the membrane, the side chains facing inside a porin monomer are prdemoninatly hydrophilic and they line the pore through which th esmall water soluble molecules move
    - - Membrane proteins have never been observed to change their topology since that would require transient movement of hydrophilic amino acid residues through bilayer which would be unfavourable
      - transmembrane glycoproteins are always orientated so all carbohydrate chains are in exoplasmic domains so they can interact with ECM, lectins, growth factors and antibodies
      - glycolipids with a carbohydrate chain attached to a glycerol or sphingosine backbone are always located in exoplasmic leaflet
  - - - cytosolic- determines shape and mechanical properties and play a role in 2 way communication between cell interior adn exterior
      - exoplasmic- bind to extracellular molecules like signalling proteins, ions and small metabolites, or attach to ECM or cell walls
    - - many peripheral proteins, like phospholipases, initially bind to the polar head groups of membrane lipidsto carry out funcitons
      - Example- phospholipase A2
        
        When in an aqueous solution, its Ca2+ containing active site is buried in a channel lined with hydrophobic amino acids
        
        The enzyme binds with greatest affinity to negatively charge phospholipids like phosphatidylserine
        
        Binding induces conformational change in the enzyme that strengthens its binding to phospholipid heads adn opens the hydrophobic channel
        
        as a phospholipid moves from the bilayer into the channel, the enzyme bound Ca2+ binds to phosphate head group which positions the ester bond to be cleaved in the catalytic site, releasing the acyl chain
  - - - acylation
        
        retention of such proteins at the membrane by N-termical acyl anchor has many funcitosn like v-Src that induces abnormal cellualr growth
        
        one group is anchored to cytosolic face by fatty acyl group (e.g. myristate or palmitate) covalently attached to N-termical Gly residue by acylation,
      - prenylation
        
        another group of proteins are anchored by hydrocarbon chain attached to CYs residue at C-terminus by prenylation
        
        prenyl anchors are built from 5-carbon isoprene units
        
        a 15-carbon farnesyl or 20 carbon geranylgeranyl group is bound by thioester to -SH group of C-terminal usually at CAAX box; after prenylation teh AAX motif may be removed by proteolysis and sometimes a second geranylgeranyl group or fatty acyl palmitate group is linked to nearby Cys residue
        
        This likely reinforces protein attachment to membrane, like Ras which is recruited to cytosolic face of plasma membrane by double anchor; or Rab proteins that are bound to cytosolic surface of vesicles and are required for vesicle fusion
  - - - bind to the exposed hydrophobic regions of membrane proteins and hydrophobic cores of water soluble proteins
      - their charge means they disrupt ionic and H bonds (sodium dodecylsulfate can completely disrupt every side chain at high concentrations)
    - - they do not generally denature proteins and so are used in extracting proteins in their folded, active form from membranes
      - at high concentrations they solubilise biologivcal membranes by forming mixed micelles of detergents, phospholipids and integral membrane proteins
      - at low concentrations they bind to hydrophobuc regions of most integral but with no micelles so the proteins remain soluble
- - - - fatty acids unlinked to CoA are bound by fatty acid binding proteins that acts as chaperones to facilitate movement (they often contain hydrophobic pocket lined by B sheets so a long fatty acid chain can fit in and interact noncovalently with protein)
      - FABP levels are high in active muscles that are using fatty acids an din adipocytes when storing or releasing fatty acids
    - - fatty acids are not directly incorporated nito phospholipids but first converted into CoA esters
      - synthesis of phospholipids are carried out by enzymes associated with cytosolic face of SER, since only on one face this creates asymmetry
      - fatty acyl CoA, glycerol 3-phosphate and polar head groups are linked and inserted into the ER membrane
      - once on ER they are transported to other organelles and plasma membrane
  - - - They are transported from the Golgi through vesicle mediated mechanisms
      - transport results in movement of both payload and the lipids composing the vesicular membrane
  - - - membrane vesicles bud from ER and fuse with Golgi complex membrane
      - but evidence suggests inter-organelle movement of cholesterol and phospholipids like, chemical inhibitors of normal pathway and mutations to impede traffic have no effect on cholesterol or phospholipid transport
      - other proposed mechanisms involve direct protein mediated contact of ER or ER-derived membranes with other organelles; adn small lipid transfer proteins that facilitate phospholipid or cholesterol movement (evidence of this is mice with knockout mutation of phosphatidylcholine transfer protein have no effects so unimportant protein)
      - cholesterol is made in Er but cholesterol concentration is 1.5 to 13 times higher in plasma membrane than in other organelles