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10-9). These peripheral proteins may serve as regulators ofmembrane-bound enzymes, or as tethers that connect integral membrane proteins to intracellular structures or limit the mobility of certain membrane proteins.Lipids attached covalently to certain membrane proteins (see Fig.10-3) anchor these proteins to the lipid bilayer by hydrophobic interactions. Proteins thus held can be released from the membrane by thebreakage of a single bond; the action of phospholipase C or D, for example, frees the membrane protein from the hydrophobic portion of aphosphatidylinositol "anchor" (see Fig.
10-9). It seems likely that thistype of quick-release mechanism gives cells the capacity to changetheir membrane surface architecture rapidly, or to alter the subcellular localization of proteins that shuttle between membrane andcytosol.Although these proteins with lipid anchors resemble integral membrane proteins in that they can be solubilized by detergent treatment,they are generally considered peripheral membrane proteins on thebasis of their other properties: their association with the membrane isoften weak and reversible, they do not contain long hydrophobic sequences, and once solubilized (by phospholipase action, for example),they behave like typical soluble proteins.MousecellMembrane Proteins Diffuse Laterally in the BilayerMany membrane proteins behave as though they were afloat in a sea oflipids.
We noted earlier that membrane lipids are free to diffuse laterally in the plane of the bilayer, and are in constant motion. The experiment diagrammed in Figure 10-12 shows that this is also true of somemembrane proteins. Other experimental techniques confirm thatmany but not all membrane proteins undergo rapid lateral diffusion,but there are many exceptions to this generalization.
Some membraneproteins associate with adjacent membrane proteins to form large aggregates ("patches") on the surface of a cell or organelle, in which indiLateral diffusionof membraneproteinsFigure 10-12 The fusion of a mouse cell with ahuman cell results in the randomization of membrane proteins from the mouse and the human cell.After fusion of the cells, the location of each type ofmembrane protein is determined by staining cellswith species-specific antibodies. Anti-mouse andanti-human antibodies are specifically tagged withmolecules that fluoresce with different colors.
Observed with the fluorescence microscope, the coloredantibodies are seen to mix on the surface of thehybrid cell within minutes after fusion, indicatingrapid diffusion of the membrane proteins throughout the lipid bilayer.Chapter 10 Biological Membranes and TransportFigure 10-13 The chloride-bicarbonate exchangeprotein of the erythrocyte spans the membrane andis tethered to the cytoskeletal protein spectrin byankyrin, limiting lateral mobility. Ankyrin containsa covalently bound palmitoyl side chain (Fig. 10-3),which may hold to the membrane. Spectrin is along, filamentous protein that forms a network attached to the cytoplasmic face of the membrane,thereby stabilizing it against deformation in shape.Chloride-bicarbonateexchange proteinsOutsideAnkyrinSpectrinJunctional complex(actin)Insidevidual protein molecules do not move relative to one another.
Acetylcholine receptors (p. 292) form dense patches at synapses. Othermembrane proteins are anchored to internal structures that preventtheir free diffusion in the membrane bilayer. In the erythrocyte membrane, both glycophorin and the chloride-bicarbonate exchanger(p.
286) are tethered from the inside to a filamentous cytoskeletal protein, spectrin (Fig. 10-13).Membrane Fusion Is Central to Many Biological ProcessesAlthough membranes are stable, they are by no means static. The fluidmosaic structure is dynamic and flexible enough to allow fusion of twomembranes.
Within the endomembrane system described in Chapter 2(see Fig. 2-10) there is constant reorganization of the membranouscompartments, as small vesicles bud from the Golgi complex carryingnewly synthesized lipids and proteins to other organelles and to theplasma membrane. Exocytosis, endocytosis, fusion of egg and spermcells, and cell division all involve membrane reorganization in whichthe fundamental operation is fusion of two membrane segments without loss of continuity (Fig. 10-14).To fuse, two membranes must first approach each other withinmolecular distances (a few nanometers).
Much evidence suggests thatan increase in intracellular Ca 2+ concentration is the signal for certainfusion events such as exocytosis. Annexins are a family of proteinslocated just beneath the plasma membrane. They bind avidly to thehead groups of phospholipids in bilayers, but only in the presence ofCa 2+ .
Some annexins also associate with specific intracellular vesiclesfated for exocytosis. These proteins cause clumping of liposomes invitro, presumably by cross-linking lipid molecules of two different vesi-Budding of vesiclesfrom Golgi complexExocytosisEndocytosisFusion of endosomeand lysosomeViral infectionFusionof sperm and eggFusion of smallvacuoles (plants)Figure 10-14 Membrane fusion is central to a variety of cellular processes, involving both organellesand the plasma membrane.Separation of twoplasma membranesat cell division281/"Part II Structure and Catalysis282Figure 10-15 One plausible model for membranefusion.
The inverted micelles shown here are onlyone kind of nonbilayer structure that might be assumed by membrane lipids. When the lipids revertto bilayer structures, either the original structure(top) or the fusion product (bottom) can form. Thefusion proteins may act by favoring the formationof the nonbilayer intermediate.JFusion proteinAnnexinAnnexins bring two membranes intoappositionFusion proteins favor temporaryformation of inverted micellesBilayers have re-formed, yieldingfused membranescles. In one simple model of membrane fusion (Fig.
10-15), annexinshold two membranes in close and stable apposition in the first step offusion.Another family of proteins believed to act in fusion is the fusionproteins, which are typified by the integral membrane protein HA,essential for the entry of the influenza virus into host cells (Fig. 10-14).(Note that these "fusion proteins" are unrelated to the products of twofused genes, also called fusion proteins, discussed in Chapter 28.) Likemost other fusion proteins, the HA protein contains two regions rich innonpolar amino acids, one a typical membrane-spanning domain, theother (the "fusion peptide") rich in Ala and Gly residues.
The fusionprotein may bridge the two membranes, with its membrane-spanningdomain in one membrane and the fusion peptide inserted into theother (Fig. 10-15).Fusion proteins may bring about transient distortions of the bilayer structure in the region of fusion. Physical studies of pure phospholipids in vitro have shown that several nonbilayer structures, suchas inverted micelles, can form under some circumstances. In the modelillustrated in Figure 10-15, an alternative structure exists in equilibrium with the bilayer, and represents the transition structure betweenunfused and fused membranes.
Fusion proteins are believed to favorthe formation of the transition structure, thus easing the phospholipidreorganization that results in fusion. In addition to annexins and fusion proteins, several, perhaps many, other proteins are probably involved; the machinery for fusion may be much more complex than implied by the simple model described here.Solute Transport across MembranesEvery living cell must acquire from its surroundings the raw materialsfor biosynthesis and for energy production, and must release to itsenvironment the byproducts of metabolism.
The plasma membranecontains proteins that specifically recognize and carry into the cellsuch necessities as sugars, amino acids, and inorganic ions. In somecases, these components are brought into the cell against a concentration gradient—"pumped" in. Certain other species are pumped out, tokeep their cytosolic concentrations lower than those in the surrounding medium. With few exceptions, the traffic of small molecules acrossthe plasma membrane occurs by protein-mediated processes, via transmembrane channels, carriers, or pumps. Within the eukaryotic cell,different compartments have different concentrations of metabolic intermediates and products, and these, too, must move across intracellular membranes in tightly regulated, protein-mediated processes.
Table10-4 summarizes the properties of membrane transport systems.Chapter 10 Biological Membranes and Transport283Table 10-4 Summary of transport typesType oftransportProteincarrier?Saturablewithsubstrate?Producesconcentrationgradient?Energydependent?SimplediffusionPassivetransport(facilitateddiffusion)ActivetransportPrimaryNoNoNoNoYesYesNoNoYesYesYesYesATP, light,substrateoxidationSecondaryYesYesYesYesIon gradientIon channelsYesNoNoNo*Energy source(if any)—ExamplesH2O, O2, N2, CH4Glucose permease oferythrocytesH+ ATPase (plantplasma membrane);Na+K+ ATPase(animal plasmamembrane)Amino acids andsugars (Na+-driven;intestine); lactose(H+-driven;bacteria)Na+ channel ofacetylcholinereceptor (plasmamembrane ofneuron)* Although the mechanism of transport via ion channels is not directly energy dependent, the direction of ion flow is determined by the transmembrane differences inelectrochemical potential. Ions always move down their electrochemical gradient through ion channels.Passive Transport Is Downhill DiffusionFacilitated by Membrane ProteinsWhen two aqueous compartments containing unequal concentrationsof a soluble compound or ion are separated by a permeable divider, thesolute moves by simple diffusion from the region of higher concentration, through the divider, to the region of lower concentration, until thetwo compartments have equal solute concentrations (Fig.
10-16). Thisbehavior of solutes is in accord with the second law of thermodynamics:molecules will tend spontaneously to assume the distribution of greatest randomness, i.e., entropy will increase.In living organisms, simple diffusion is impeded by selectively permeable barriers—the membranes that separate intracellular compartments and surround cells. To pass through the bilayer, a polar orcharged solute must give up its interactions with the water moleculesin its hydration shell, then diffuse about 3 nm through a solvent inwhich it is poorly soluble (the central region of the lipid bilayer), beforereaching the other side and regaining its water of hydration (Fig.10-17). The energy used to strip away the hydration shell and move apolar compound from water into lipid is regained as the compoundleaves the membrane on the other side and is rehydrated.
However,the intermediate stage of transmembrane passage represents a high-Figure 10—16 The rate of net movement of a solute across a permeable membrane depends uponthe size of the concentration gradient. Cx and C2are the solute concentrations on the left and rightsides of the membrane.Part II Structure and Catalysis284HydratedsoluteSimple diffusionwithout transporter(b)TransporterFigure 10-17 Energy changes that occur as a solute in aqueous solution passes through the lipidbilayer of a biological membrane, (a) In simple diffusion, the removal of the hydration shell is highlyendergonic, and the energy of activation (AG*) fordiffusion through the bilayer is very high, (b) Atransporter protein—by forming noncovalent interactions with the dehydrated solute to replace itshydrogen bonds with water, and by providing ahydrophilic transmembrane passageway—reducesthe AG^ for transmembrane diffusion of the solute.Glucose in blood[S]out ~ 5 mMIntracellular glucose[S]in < 5 HIMEnergy-yieldingmetabolismFigure 10—18 The glucose permease of erythrocytes facilitates the passage of glucose into the cell,down its concentration gradient.
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