H. Lodish - Molecular Cell Biology (5ed, Freeman, 2003) (796244), страница 67
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Such transmembrane glycoproteins are always oriented so that the carbohydrate chainsare in the exoplasmic domain (see Figures 5-11 and 5-12).Likewise, glycolipids, in which a carbohydrate chain is attached to the glycerol or sphingosine backbone, are alwayslocated in the exoplasmic leaflet with the carbohydrate chainprotruding from the membrane surface. Both glycoproteinsand glycolipids are especially abundant in the plasma membranes of eukaryotic cells; they are absent from the inner mitochondrial membrane, chloroplast lamellae, and severalother intracellular membranes. Because the carbohydratechains of glycoproteins and glycolipids in the plasma membrane extend into the extracellular space, they are availableto interact with components of the extracellular matrix aswell as lectins, growth factors, and antibodies.One important consequence of such interactionsis illustrated by the A, B, and O blood-groupantigens.
These three structurally related oligosaccharide components of certain glycoproteins and glycolipids are expressed on the surfaces of human erythrocytesand many other cell types (Figure 5-16). All humans havethe enzymes for synthesizing O antigen. Persons with typeA blood also have a glycosyltransferase that adds an extra162CHAPTER 5 • Biomembranes and Cell ArchitectureLipid orproteinGlcGalGlcNAcGlcGalGlcNAcGlcGalA antigenO antigenGalFucGaltransferaseLipid orproteinGalNAcFucGalNActransferaseLipid orproteinGalGlcNAcGlc = GlucoseGal = GalactoseGlcNAc = N -AcetylglucosamineGalNAc = N -AcetylgalactosamineFuc = FucoseGalGalB antigenFuc▲ FIGURE 5-16 Human ABO blood-group antigens.
Theseantigens are oligosaccharide chains covalently attached toglycolipids or glycoproteins in the plasma membrane. Theterminal oligosaccharide sugars distinguish the three antigens.The presence or absence of the glycosyltransferases that addgalactose (Gal) or N-acetylgalactosamine (GalNAc) to O antigendetermine a person’s blood type.N-acetylgalactosamine to O antigen to form A antigen.Those with type B blood have a different transferase thatadds an extra galactose to O antigen to form B antigen. People with both transferases produce both A and B antigen(AB blood type); those who lack these transferases produceO antigen only (O blood type).Persons whose erythrocytes lack the A antigen, B antigen, or both on their surface normally have antibodiesagainst the missing antigen(s) in their serum.
Thus if a typeA or O person receives a transfusion of type B blood, antibodies against the B epitope will bind to the introduced redcells and trigger their destruction. To prevent such harmfulreactions, blood-group typing and appropriate matching ofblood donors and recipients are required in all transfusions(Table 5-2).
❚Interactions with the Cytoskeleton Impedethe Mobility of Integral Membrane ProteinsThe results of experiments like the one depicted in Figure5-6 and other types of studies have shown that many transmembrane proteins and lipid-anchored proteins, like phospholipids, float quite freely within the plane of a naturalmembrane. From 30 to 90 percent of all integral proteinsin the plasma membrane are freely mobile, depending on thecell type. The lateral diffusion rate of a mobile protein in apure phospholipid bilayer or isolated plasma membrane issimilar to that of lipids. However, the diffusion rate of aprotein in the plasma membrane of intact cells is generally10–30 times lower than that of the same protein embeddedin synthetic spherical bilayer structures (liposomes).
Thesefindings suggest that the mobility of integral proteins in theplasma membrane of living cells is restricted by interactionswith the rigid submembrane cytoskeleton. Some integralproteins are permanently linked to the underlying cytoskeleton; these proteins are completely immobile in themembrane. In regard to mobile proteins, such interactionsare broken and remade as the proteins diffuse laterally inthe plasma membrane, slowing down their rate of diffusion.We consider the nature and functional consequences of linkages between integral membrane proteins and the cytoskeleton in Chapter 6.Lipid-Binding Motifs Help Target PeripheralProteins to the MembraneUntil the past decade or so, the interaction of peripheralproteins with integral proteins was thought to be the majorTABLE 5-2 ABO Blood GroupsBlood-GroupTypeAntigens onRBCs*Serum AntibodiesCan ReceiveBlood TypesAAAnti-AA and OBBAnti-BB and OABA and BNoneAllOOAnti-A and anti-BO*See Figure 5-16 for antigen structures.5.2 • Biomembranes: Protein Components and Basic Functions163TABLE 5-3 Selected Lipid-Binding MotifsMotifLigand*Selected Proteins with MotifPHPIP2, PIP3Phospholipase C1, protein kinase B, pleckstrinC2Acidic phospholipidsProtein kinase C, PI-3 kinase, phospholipase, PTENphosphataseAnkyrin repeatPSAnkyrin†FERMPIP2Band 4.1 protein; ezrin, radixin, moesin (ERM)†*PIP2, PIP3, and PI-3P phosphatidylinositol derivatives with additional phosphate groups on the inositol ring (see Figure 14-26); PH pleckstrin homology; PS phosphatidylserine;.†These proteins have roles in linking the actin cytoskeleton to the plasma membrane.(a)NH3CH2CH2OActivesiteOPO−.
. Ca2+O...mechanism by which peripheral proteins were bound tomembranes. The results of more recent research indicatethat protein–lipid interactions are equally important inlocalizing peripheral proteins to cellular membranes (seeFigure 5-11).Analyses of genome sequences have revealed severalwidely distributed lipid-binding motifs in proteins (Table5-3). For instance, the pleckstrin homology (PH) domain,which binds two types of phosphorylated phosphatidylinositols, is the eleventh most common protein domain encoded in the human genome. This domain was initiallyrecognized in pleckstrin, a protein found in platelets.
Thehigh frequency of the PH domain indicates that proteinslocalized to membrane surfaces carry out many importantfunctions. Other common lipid-binding motifs include theC2 domain, the ankyrin-repeat domain, and the FERMdomain. Originally discovered in protein kinase C, the C2domain is a membrane-targeting domain for various kinases,phosphatases, and phospholipases.The phospholipases are representative of those watersoluble enzymes that associate with the polar head groups ofmembrane phospholipids to carry out their catalytic functions. As noted earlier, phospholipases hydrolyze variousbonds in the head groups of phospholipids (see Figure 5-9).These enzymes have an important role in the degradationof damaged or aged cell membranes and are active molecules in many snake venoms. The mechanism of action ofphospholipase A2 illustrates how such water-soluble enzymes can reversibly interact with membranes and catalyzereactions at the interface of an aqueous solution and lipidsurface.
When this enzyme is in aqueous solution, its Ca2containing active site is buried in a channel lined with hydrophobic amino acids. The enzyme binds with greatestaffinity to bilayers composed of negatively charged phospholipids (e.g., phosphotidylethanolamine). This findingsuggests that a rim of positively charged lysine and arginineresidues around the entrance catalytic channel is particularlyimportant in interfacial binding (Figure 5-17a). BindingOCH2(b)Ca2+CHOCCH2OCOR1R2▲ FIGURE 5-17 Interfacial binding surface and mechanismof action of phospholipase A2.
(a) A structural model of theenzyme showing the surface that interacts with a membrane.This interfacial binding surface contains a rim of positivelycharged arginine and lysine residues shown in blue surroundingthe cavity of the catalytic active site in which a substrate lipid(red stick structure) is bound.
(b) Diagram of catalysis byphospholipase A2. When docked on a model lipid membrane,positively charged residues of the interfacial binding site bind tonegatively charged polar groups at the membrane surface. Thisbinding triggers a small conformational change, opening achannel lined with hydrophobic amino acids that leads from thebilayer to the catalytic site. As a phospholipid moves into thechannel, an enzyme-bound Ca2+ ion (green) binds to the headgroup, positioning the ester bond to be cleaved next to thecatalytic site.
[Part (a) adapted from M. H. Gelb et al., 1999, Curr. Opin.Struc. Biol. 9:428. Part (b), see D. Blow, 1991, Nature 351:444.]164CHAPTER 5 • Biomembranes and Cell Architectureinduces a small conformational change in phospholipase A2that fixes the protein to the phospholipid heads and opensthe hydrophobic channel. As a phospholipid molecule diffuses from the bilayer into the channel, the enzyme-boundCa2 binds to the phosphate in the head group, thereby positioning the ester bond to be cleaved next to the catalytic site(Figure 5-17b).The Plasma Membrane Has Many CommonFunctions in All CellsAlthough the lipid composition of a membrane largely determines its physical characteristics, its complement of proteins is primarily responsible for a membrane’s functionalproperties.
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