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Ch 11: Biological Membranes and Transport, 11.3 Solute Transport across…

- - - - simple diffusion: movement of a solute form the region of higher concentration to the region of lower concentration
      - definition: facilitate movement down a concentration gradient, increasing the transport rate
      - process is called passive transport of facilitated diffusion
      - ex: the glucose transporter of erythrocytes
        
        glucose enters the erythrocyte by passive transport via GLUT1
        
        rate equation analogous to MIchaelis-Menten
        
        GLUT1: integral membrane protein with 12 hydrophobic segments that form 12 membrane-spanning amphipathic helices
        
        model of of this cycles between two extreme conformations:
        
        T1 form: glucose-binding site is exposed on the outer membrane surface
        
        T2 form: glucose-binding site is exposed on the inner surface
        
        transport of glucose into a myocyte by GLUT4 is regulated by insulin:
        
        Glucose transporters are "stored" within the cell in membrane vesicles.
        
        When insulin interacts with its receptor, vesicles move to the surface and fuse with the PM, increasing the number of glucose transporters in the PM.
        
        When insulin level drops, glucose transporters are removed from the PM by endocytosis, forming small vesicles.
        
        The smaller vesicles fuse with a larger endosome.
        
        Patches of the endosome enriched with glucose transporters bud off to become small vesicles, ready to return to the surface when insulin levels rise again.
      - ex: the chloride-bicarbonate exchanger catalyzes electroneutral cotransport of anions across the PM
        
        chloride-bicarbonate exchanger: anion exchanger essential in CO2 transport to the longs from tissues
        
        electroneutral exchange: no net transfer of charge
        
        antiporter
    - - definition: move substrates across a membrane against a concentration gradient or an electrical potential
      - process is called active transport
      - types:
        
        primary active transporters
        
        solute accumulation is coupled directly to an exergonic chemical reaction
        
        secondary active transporters
        
        endergonic transport of one solute is coupled to the exergonic flow of a different solute that was originally pumped uphill by primary active transport
        
        Ion gradients provide the energy for secondary active transport
        
        ex: Na+-glucose symporter: takes up glucose from the intestine in a process driven by the downhill flow of Na+
        
        ionophores: compounds that shuttle ions across membranes down an electrochemical gradient
        
        ex: the peptide ionophore valinomycin, an antibiotic
        
        acts as a shuttle, carrying K+ across the membrane down its concentration gradient and deflating that gradient
      - results in solute movement against a concentration or electrochemical gradient
        
        results in the accumulation of a solute above the equilibrium opint
        
        thermodynamically unfavorable (endergonic); must be directly or indirectly coupled to an exergonic process
  - - - opposes ion movements that increase Vm
      - drives movements that reduce Vm
  - - - the chemical gradient
      - the electrical gradient
  - - - forming noncovalent interactions with the dehydrated solute
      - providing a hydrophilic transmembrane pathway
    - - definition: provide an aqueous path across the membrane through which inorganic ions can diffuse at very high rates
      - most have a "gate" regulated by a biological signal
      - typically show some specificity for an ion
      - flow stops either when the gate is closed or when there is no longer an electrochemical gradient
  - - - antiport systems: moves in opposite directions
      - symport systems: move in the same direction
  - - - electrogenic: producing an electrical potential
      - free energy change for transport, deltaGt, of an ion is the sum of the chemical and electrical gradients, where Z is the charge of the ion, F is the Faraday constant, and deltapsi is the transmembrane electrical potential
- - - - integral proteins with 8 or 10 predicted membrane-spanning regions
      - sensitive to inhibition by the transition-state analog vanadate
      - ex: SERCA pump and PM Ca2+ ATPase pump: uniporters for Ca2+ ions
        
        postulated mechanism of the SERCA Pump:
        
        each catalytic cycle moves two Ca2+ ions across the membrane and converts an ATP to ADP and Pi
        
        two conformations of the transporter, E1 and E2, interconvert
      - critical Asp residue in the P domain undergoes phosphorylation and dephosphorylation
      - role of Na+K+ATPase in Animal cells:
        
        couples phosphorylation-dephosphorylation of the critical Asp residue to the movement of Na+ and K+ against their electrochemical gradients
        
        maintains low [Na+] and high [K+] in the cell
        
        essential to the conduction of action potential in neurons
      - definition: family of cation transporters that are reversibly phosphorylated by ATP as part of the transport cycle
  - - - large proton gradient can supply the energy to drive ATP synthesis
      - when functioning in this direction, F-type ATPases are named ATP synthases
- - - - encoded by the ABCB1 gene
      - removes toxic compounds
      - responsible for resistance fo tumors to drugs
- - - - long-chain saturated fatty acids tend to pack into an Lo phase
      - kinks in unsaturated fatty acids interfere with packing, favoring the Ld state
      - shorter-chain fatty acyl groups favor the Ld state
  - - - they interact with phospholipids containing unsaturated fatty acyl chains, compacting them and constraining their motion
      - they associate with sphingolipids and phospholipids having long, saturated fatty acyl chains, making the bilayer fluid
- - - - definition: catalyze translocation of the amino-phospholipids PI and PS from the extracellular to the cytoplasmic leaflet of the plasma membrane
      - consume about 1 ATP per molecule of phospholipid translocated
      - related ot the P-type ATPases (active transporters)
    - - definition: move PM phospholipids and sterols from the cytoplasmic leaflet to the extracellular leaflet
      - ATP-dependent
      - each specializes in movement of specific lipids
    - - definition: move any membrane phospholipid across the bilayer down its concentration gradient
      - not dependent on ATP; some require Ca2+
      - lead to controlled randomization of the head-group composition on the two faces of the bilayer
    - - definition: move phosphatidylinositol lipids across lipid bilayers
      - believed to have roles in lipid signaling and membrane trafficking
- - - - sphingolipids and cholesterol cluster together in membrane rafts
        
        microdomains (rafts)
        
        definition: clusters of cholesterol and sphingolipids that make the bilayer slightly thicker and more ordered than neighboring, phospholipid-rich regions
        
        can by up to 50% of the cell surface
        
        relate to proteins...
        
        proteins must have hydrophobic helical sections long enough to segregate into the thicker bilayer regions of rafts
        
        lipid rafts are enriched in:
        
        proteins that have two long-chain saturated fatty acids covalently attached through Cys residues
        
        GPI-anchored proteins
        
        caveolin: integral protein that binds to cytoplasmic leaflet of PM
        
        forms dimers
        
        associates with cholesterol-rich membrane regions
        
        forces the bilayer to curve inward to form caveolae ("little caves," specialized rafts)
- - - - definition: domains consisting of coiled coils that form long, thin, curved dimers with a positively charged concave surface
      - BAR domain proteins assemble into crescent-shaped scaffolds and favor membrane curvature
    - - definition: family of GTP-binding proteins that polymerize at curved regions of the PM
      - participate in cell division, exocytosis, phagocytosis, and apoptosis
      - have an amphipathic helix that is important in vesicle trafficking and neurotransmitter release
    - - v-SNAREs: SNAREs in the cytoplasmic face of the intracellular vesicle
      - t-SNAREs: SNAREs in the target membrane with which the vesicle fuses
- - - - favored when the cross-sectional are of the head group is greater than that of the acyl side chain(s)
      - definition: spherical structures containing amphipathic molecules arranged with hydrophobic regions in the interior and hydrophilic head groups on the exterior
    - - favored when the cross-sectional areas of the head group and acyl side chains are similar
      - definition: lipid aggregate in which two lipid monolayers (leaflets) form a two-dimensional sheet
  - - - definition: pattern formed by individual lipid and protein units in a membrane
      - pattern can change while maintaining the permeability membrane
- - - - definition: attachment of oligosaccharides to proteins
      - typically on the outer face of the PM
  - - - peripheral membrane proteins: associate with the membrane through electrostatic interactions and hydrogen bonding
      - amphitropic proteins: associate reversibly with membranes
      - integral membrane proteins: firmly embedded within the lipid bilayer
        
        topology of integral proteins can often be predicted from their sequence
        
        an alpha-helical sequence of 20-25 residues is just long enough to span the thickness of the lipid bilayer
        
        stabilized by intrachain hydrogen bonding and the hydrophobic effect
        
        hydropathy
        
        hydropathy index
        
        ranges from highly exergonic to highly endergonic
        
        overall hydropathy index: estimated by summing the free energies of transfer for the residues in the sequence
        
        definition: expresses the free-energy change associated with the movement of an amino acid side chain from a hydrophobic environment to water
        
        hydropathy plot
        
        definition: average hydropathy index plotted against residue number
        
        parts:
        
        window: segment of given length
        
        hydropathy index (y-axis): average hydropathy for a window
        
        residue number (x-axis): the residue in the middle of the window
        
        a region with more than 20 residues of high hydropathy index is presumed to be a transmembrane segment
        
        beta structure
        
        beta barrel
        
        definition: structural motif in which 20+ transmembrane segments form beta sheets that line a cylinder
        
        stabilized by intrachain hydrogen bonds
        
        part of porins
        
        definition: proteins that allow certain polar solutes to cross the outer membrane of gram-negative bacteria
        
        have beta barrels lining the transmembrane passage
        
        beta strands
        
        in beta conformation,
        
        seven to nine residues are needed to span a membrane
        
        alternating side chains project above and below the sheet
        
        in beta strands of membrane proteins,
        
        every second residue in the membrane-spanning segment is hydrophobic and interacts with the lipid bilayer
        
        aromatic side chains are commonly found at the lipid-protein interface
        
        amino acid locations relative to the bilayer:
        
        Tyr and Trp side chains serve as membrane interface anchors
        
        positive-inside rule: positively charged Lys and Arg residues in the extramembrane loop of membrane proteins occur more commonly on the cytoplasmic face
        
        in many organisms, 20-30% of proteins are integral proteins
    - - monotopic proteins
        
        definition: have small hydrophobic domains that interact with only a single leaflet of the membrane
      - bitopic proteins
        
        definition: span the bilayer once, extending on either surface
        
        have a single hydrophobic sequence somewhere in the molecule
      - polytopic proteins
        
        definition: cross the membrane several times
        
        have multiple hydrophobic sequences of ~20 residues that each cross the membrane when in the alpha helical conformation
    - - GPI-anchored protein: exclusively on the outer face and are clustered in certain regions
- - - - golgi apparatus
      - lysosomes
      - various small vesicles
      - endoplasmic reticulum (ER)
    - - nucleus
      - mitochondrion
      - chloroplasts