H. Lodish - Molecular Cell Biology (5ed, Freeman, 2003) (796244), страница 66
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(b) Molecular model of the transmembrane domain ofdimeric glycophorin corresponding to residues 73–96. The sidechains of the helix in one monomer are shown in red; those inthe other monomer, in gray. Residues depicted as space-fillingstructures participate in intermonomer van der Waals interactionsthat stabilize the coiled-coil dimer. [Part (b) adapted from K. R.MacKenzie et al., 1997, Science 276:131.]of other subunits, forming a central channel (see Figure7-15). Polar and hydrophobic residues lining the center ofthe bundle form a channel in the membrane, but as with bacteriorhodopsin virtually all of the amino acids on the exteriorof the membrane-spanning domain are hydrophobic.
Inmany ion channels, external factors (e.g., a ligand, voltage,or mechanical strain) regulate ion flow across the bilayer byreorienting the helices. Details of ion channels and theirstructures are discussed in Chapter 7. FIGURE 5-13 Structural model of bacteriorhodopsin, aCytosolmultipass transmembrane protein that functions as aphotoreceptor in certain bacteria. The seven hydrophobic helices in bacteriorhodopsin traverse the lipid bilayer.
A retinalmolecule (red) covalently attached to one helix absorbs light. Thelarge class of G protein–coupled receptors in eukaryotic cells alsohas seven membrane-spanning helices; their three-dimensionalstructure is similar to that of bacteriorhodopsin. [After H. Luecke etal., 1999, J. Mol. Biol. 291:899.]160CHAPTER 5 • Biomembranes and Cell ArchitectureMultiple Strands in Porins FormMembrane-Spanning “Barrels”The porins are a class of transmembrane proteins whosestructure differs radically from that of other integral proteins.
Several types of porin are found in the outer membraneof gram-negative bacteria such as E. coli and in the outermembranes of mitochondria and chloroplasts. The outermembrane protects an intestinal bacterium from harmfulagents (e.g., antibiotics, bile salts, and proteases) but permits the uptake and disposal of small hydrophilic moleculesincluding nutrients and waste products. The porins in theouter membrane of an E. coli cell provide channels for thepassage of disaccharides and other small molecules as well asphosphate.The amino acid sequences of porins are predominantlypolar and contain no long hydrophobic segments typical ofintegral proteins with -helical membrane-spanning domains.
X-ray crystallography has revealed that porins aretrimers of identical subunits. In each subunit, 16 strandsform a barrel-shaped structure with a pore in the center (Fig-ExteriorPeriplasm▲ FIGURE 5-14 Structural model of one subunit of OmpX,a porin found in the E. coli outer membrane. All porins aretrimeric transmembrane proteins. Each subunit is barrel shaped,with strands forming the wall and a transmembrane pore in thecenter. A band of aliphatic (noncyclic) side chains (yellow) and aborder of aromatic (ring-containing) side chains (red) position theprotein in the bilayer. [After G.
E. Schulz, 2000, Curr. Opin. Struc. Biol.10:443.]ure 5-14). Unlike a typical water-soluble globular protein, aporin has a hydrophilic inside and a hydrophobic exterior; inthis sense, porins are inside-out. In a porin monomer, theoutward-facing side groups on each of the strands are hydrophobic and form a nonpolar ribbonlike band that encircles the outside of the barrel. This hydrophobic bandinteracts with the fatty acyl groups of the membrane lipids orwith other porin monomers. The side groups facing the inside of a porin monomer are predominantly hydrophilic;they line the pore through which small water-soluble molecules cross the membrane.As discussed in Chapter 7, the plasma membranes of animal cells contain a water channel called aquaporin. Like mostother integral proteins, aquaporin contains multiple transmembrane helices.
Thus, despite its name, aquaporin differsstructurally from the porins as well as functionally in that itmediates transport of a single molecule—namely, water.Covalently Attached Hydrocarbon Chains AnchorSome Proteins to MembranesIn eukaryotic cells, several types of covalently attached lipidsanchor some proteins to one or the other leaflet of theplasma membrane and certain other cellular membranes. Inthese lipid-anchored proteins, the lipid hydrocarbon chainsare embedded in the bilayer, but the protein itself does notenter the bilayer.A group of cytosolic proteins are anchored to the cytosolic face of a membrane by a fatty acyl group (e.g., myristateor palmitate) attached to the N-terminal glycine residue (Figure 5-15a).
Retention of such proteins at the membrane bythe N-terminal acyl anchor may play an important role in amembrane-associated function. For example, v-Src, a mutantform of a cellular tyrosine kinase, is oncogenic and can transform cells only when it has a myristylated N-terminus.A second group of cytosolic proteins are anchored tomembranes by an unsaturated fatty acyl group attached toa cysteine residue at or near the C-terminus (Figure 5-15b).In these proteins, a farnesyl or geranylgeranyl group is boundthrough a thioether bond to the OSH group of a C-terminalcysteine residue. These prenyl anchors are built from isopreneunits (C5), which are also used in the synthesis of cholesterol(Chapter 18).
In some cases, a second geranylgeranyl groupor a palmitate group is linked to a nearby cysteine residue.The additional anchor is thought to reinforce the attachmentof the protein to the membrane. Ras, a GTPase superfamilyprotein that functions in intracellular signaling, is localized tothe cytosolic face of the plasma membrane by such a doubleanchor. Rab proteins, which also belong to the GTPase superfamily, are similarly bound to the cytosolic surface of intracellular vesicles by prenyl-type anchors; these proteins arerequired for the fusion of vesicles with their target membranes(Chapter 17).Some cell-surface proteins and heavily glycosylated proteoglycans of the extracellular matrix are bound to the exo-5.2 • Biomembranes: Protein Components and Basic Functions+H N3(c) GPI anchor161As already discussed, PLAP is concentrated in lipid rafts,the more ordered bilayer microdomains that are enriched insphingolipids and cholesterol (see Figure 5-10).
AlthoughPLAP and other GPI-anchored proteins lie in the oppositemembrane leaflet from acyl-anchored proteins, both types ofmembrane proteins are concentrated in lipid rafts. In contrast, prenylated proteins are not found in lipid rafts.ExteriorAll Transmembrane Proteins and GlycolipidsAre Asymmetrically Oriented in the BilayerCytosolGlyCysNH3+COO−(a) Acylation(b) Prenylation▲ FIGURE 5-15 Anchoring of plasma-membrane proteins tothe bilayer by covalently linked hydrocarbon groups.(a) Cytosolic proteins such as v-Src are associated with theplasma membrane through a single fatty acyl chain attached tothe N-terminal glycine (Gly) residue of the polypeptide. Myristate(C14) and palmitate (C16) are common acyl anchors. (b) Othercytosolic proteins (e.g., Ras and Rab proteins) are anchored tothe membrane by prenylation of one or two cysteine (Cys)residues, at or near the C-terminus.
The anchors are farnesyl(C15) and geranylgeranyl (C20) groups, both of which areunsaturated. (c) The lipid anchor on the exoplasmic surface of theplasma membrane is glycosylphosphatidylinositol (GPI). Thephosphatidylinositol part (red) of this anchor contains two fattyacyl chains that extend into the bilayer. The phosphoethanolamineunit (purple) in the anchor links it to the protein. The two greenhexagons represent sugar units, which vary in number andarrangement in different GPI anchors. The complete structure of ayeast GPI anchor is shown in Figure 16-14. [Adapted from H.
Spronget al., 2001, Nature Rev. Mol. Cell Biol. 2:504.]plasmic face of the plasma membrane by a third type of anchor group, glycosylphosphatidylinositol (GPI). The exactstructures of GPI anchors vary greatly in different cell types,but they always contain phosphatidylinositol (PI), whose twofatty acyl chains extend into the lipid bilayer; phosphoethanolamine, which covalently links the anchor to theC-terminus of a protein; and several sugar residues (Figure5-15c). Various experiments have shown that the GPI anchoris both necessary and sufficient for binding proteins to themembrane. For instance, the enzyme phospholipase C cleavesthe phosphate–glycerol bond in phospholipids and in GPI anchors (see Figure 5-9).
Treatment of cells with phospholipaseC releases GPI-anchored proteins such as Thy-1 and placentalalkaline phosphatase (PLAP) from the cell surface.Lipid-anchored proteins are just one example of membraneproteins that are asymmetrically located with respect to thefaces of cellular membranes. Each type of transmembraneprotein also has a specific orientation with respect to themembrane faces. In particular, the same part(s) of a particular protein always faces the cytosol, whereas other parts facethe exoplasmic space. This asymmetry in protein orientationconfers different properties on the two membrane faces.
(Wedescribe how the orientation of different types of transmembrane proteins is established during their synthesis in Chapter 16.) Membrane proteins have never been observed toflip-flop across a membrane; such movement, requiring atransient movement of hydrophilic amino acid residuesthrough the hydrophobic interior of the membrane, wouldbe energetically unfavorable. Accordingly, the asymmetry ofa transmembrane protein, which is established during itsbiosynthesis and insertion into a membrane, is maintainedthroughout the protein’s lifetime.Many transmembrane proteins contain carbohydratechains covalently linked to serine, threonine, or asparagineside chains of the polypeptide.
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