H. Lodish - Molecular Cell Biology (5ed, Freeman, 2003) (796244), страница 65
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Protein domains on the extracellular surface of theplasma membrane generally bind to other molecules, including external signaling proteins, ions, and small metabolites(e.g., glucose, fatty acids), and to adhesion molecules on157other cells or in the external environment. Domains withinthe plasma membrane, particularly those that form channelsand pores, move molecules in and out of cells. Domains lyingalong the cytosolic face of the plasma membrane have a widerange of functions, from anchoring cytoskeletal proteins tothe membrane to triggering intracellular signaling pathways.In many cases, the function of a membrane protein andthe topology of its polypeptide chain in the membrane can bepredicted on the basis of its homology with another, wellcharacterized protein.
In this section, we examine the characteristic structural features of membrane proteins and someof their basic functions. More complete characterization ofthe structure and function of various types of membrane proteins is presented in several later chapters; the synthesis andprocessing of this large, diverse group of proteins are discussed in Chapters 16 and 17.Proteins Interact with Membranesin Three Different WaysMembrane proteins can be classified into three categories—integral, lipid-anchored, and peripheral—on the basis of thenature of the membrane–protein interactions (Figure 5-11).Integral membrane proteins, also called transmembraneproteins, span a phospholipid bilayer and are built of threesegments.
The cytosolic and exoplasmic domains have hydrophilic exterior surfaces that interact with the aqueoussolutions on the cytosolic and exoplasmic faces of the membrane. These domains resemble other water-soluble proteinsin their amino acid composition and structure.
In contrast,the 3-nm-thick membrane-spanning domain contains manyhydrophobic amino acids whose side chains protrude outward and interact with the hydrocarbon core of the phospholipid bilayer. In all transmembrane proteins examined todate, the membrane-spanning domains consist of one or more helices or of multiple strands. In addition, most transmembrane proteins are glycosylated with a complex branchedsugar group attached to one or several amino acid side chains.Invariably these sugar chains are localized to the exoplasmicdomains.Lipid-anchored membrane proteins are bound covalentlyto one or more lipid molecules.
The hydrophobic carbonchain of the attached lipid is embedded in one leaflet of themembrane and anchors the protein to the membrane. Thepolypeptide chain itself does not enter the phospholipidbilayer.Peripheral membrane proteins do not interact with thehydrophobic core of the phospholipid bilayer. Instead theyare usually bound to the membrane indirectly by interactionswith integral membrane proteins or directly by interactionswith lipid head groups. Peripheral proteins are localized toeither the cytosolic or the exoplasmic face of the plasmamembrane.In addition to these proteins, which are closely associatedwith the bilayer, cytoskeletal filaments are more loosely associated with the cytosolic face, usually through one or more158CHAPTER 5 • Biomembranes and Cell Architecture FIGURE 5-11 Diagram of how variousclasses of proteins associate with the lipidbilayer.
Integral (transmembrane) proteinsspan the bilayer. Lipid-anchored proteins aretethered to one leaflet by a long covalentlyattached hydrocarbon chain. Peripheralproteins associate with the membraneprimarily by specific noncovalent interactionswith integral proteins or membrane lipids.Farther from the membrane are membraneassociated proteins including thecytoskeleton, extracellular matrix in animalcells, and cell wall in plant and bacterialcells (not depicted).
Carbohydrate chains areattached to many extracellular proteins andto the exoplasmic domains of manytransmembrane proteins.Extracellular matrixPeripheralLipidanchoredExteriorIntegralIntegralCytosolperipheral (adapter) proteins (see Figure 5-11). Such associations with the cytoskeleton provide support for various cellular membranes (see Section 5.4); they also play a role in thetwo-way communication between the cell interior and thecell exterior, as we learn in Chapter 6.
Finally, peripheralproteins on the outer surface of the plasma membrane andthe exoplasmic domains of integral membrane proteins areoften attached to components of the extracellular matrix orto the cell wall surrounding bacterial and plant cells.Membrane-Embedded Helices Arethe Primary Secondary Structuresin Most Transmembrane ProteinsSoluble proteins exhibit hundreds of distinct localized foldedstructures, or motifs (see Figure 3-6). In comparison, therepertoire of folded structures in integral membrane proteinsis quite limited, with the hydrophobic helix predominating.Integral proteins containing membrane-spanning -helicaldomains are embedded in membranes by hydrophobic interactions with specific lipids and probably also by ionic interactions with the polar head groups of the phospholipids.Glycophorin A, the major protein in the erythrocyteplasma membrane, is a representative single-pass transmembrane protein, which contains only one membrane-spanning helix (Figure 5-12).
Typically, a membrane-embedded helix is composed of 20–25 hydrophobic (uncharged) aminoacids (see Figure 2-13). The predicted length of such a helix(3.75 nm) is just sufficient to span the hydrocarbon core ofa phospholipid bilayer. The hydrophobic side chains protrude outward from the helix and form van der Waals interactions with the fatty acyl chains in the bilayer.
In contrast, the carbonyl (CUO) and imino (NH) groups takingpart in the formation of backbone peptide bonds throughPeripheralPeripheralCytoskeletonhydrogen bonding are in the interior of the helix (seeFigure 3-3); thus these polar groups are shielded from thehydrophobic interior of the membrane. The transmembrane helix of one glycophorin A molecule associates withthe helix in another to form a coiled-coil dimer (see Figure5-12b). Such interaction of membrane-spanning helices is acommon mechanism for creating dimeric membrane proteins. Many cell-surface receptors, for instance, are activatedby dimerization.A large and important family of integral proteins is defined by the presence of seven membrane-spanning helices. Among the more than 150 such “seven spanning”multipass proteins that have been identified are the G protein–coupled receptors described in Chapter 13.
The structure of bacteriorhodopsin, a protein found in the membraneof certain photosynthetic bacteria, illustrates the generalstructure of all these proteins (Figure 5-13). Absorption oflight by the retinal group covalently attached to bacteriorhodopsin causes a conformational change in the proteinthat results in the pumping of protons from the cytosolacross the bacterial membrane to the extracellular space.The proton concentration gradient thus generated across themembrane is used to synthesize ATP (Chapter 8). In thehigh-resolution structure of bacteriorhodopsin now available, the positions of all the individual amino acids, retinal,and the surrounding lipids are determined.
As might be expected, virtually all of the amino acids on the exterior ofthe membrane-spanning segments of bacteriorhodopsin arehydrophobic and interact with the hydrocarbon core of thesurrounding lipid bilayer.Ion channels compose a second large and important family of multipass transmembrane proteins. As revealed by thecrystal structure of a resting K channel, ion channels aretypically tetrameric proteins. Each of the four subunits hasa pair of membrane-spanning helices that bundle with helices5.2 • Biomembranes: Protein Components and Basic Functions(a)159(b)ExtracellulardomainNN73Membranespanninghelices96CCCytosolicdomain▲ FIGURE 5-12 Structure of glycophorin A, a typical singlepass transmembrane protein.
(a) Diagram of dimericglycophorin showing major sequence features and its relation tothe membrane. The single 23-residue membrane-spanning helixin each monomer is composed of amino acids with hydrophobic(uncharged) side chains (red spheres). By binding negativelycharged phospholipid head groups, the positively chargedarginine and lysine residues (blue spheres) near the cytosolicside of the helix help anchor glycophorin in the membrane. Boththe extracellular and the cytosolic domains are rich in chargedExteriorresidues and polar uncharged residues; the extracellular domainis heavily glycosylated, with the carbohydrate side chains (greendiamonds) attached to specific serine, threonine, and asparagineresidues.
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