Membrane Embedded a Helices Are the Primary Secondary Structures in Most Transmembrane Proteins

Soluble proteins exhibit hundreds of distinct localized folded structures, or motifs (see Figure 3-6). In comparison, the repertoire of folded structures in integral membrane proteins is quite limited, with the hydrophobic a helix predominating. Integral proteins containing membrane-spanning a-helical domains 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 erythrocyte plasma membrane, is a representative single-pass transmembrane protein, which contains only one membrane-spanning a helix (Figure 5-12). Typically, a membrane-embedded a helix is composed of 20-25 hydrophobic (uncharged) amino acids (see Figure 2-13). The predicted length of such a helix (3.75 nm) is just sufficient to span the hydrocarbon core of a 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 (C=O) and imino (NH) groups taking part in the formation of backbone peptide bonds through hydrogen bonding are in the interior of the a helix (see Figure 3-3); thus these polar groups are shielded from the hydrophobic interior of the membrane. The transmembrane helix of one glycophorin A molecule associates with the helix in another to form a coiled-coil dimer (see Figure 5-12b). Such interaction of membrane-spanning helices is a common mechanism for creating dimeric membrane proteins. Many cell-surface receptors, for instance, are activated by dimerization.

A large and important family of integral proteins is defined by the presence of seven membrane-spanning a 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 membrane of certain photosynthetic bacteria, illustrates the general structure of all these proteins (Figure 5-13). Absorption of light by the retinal group covalently attached to bacteri-orhodopsin causes a conformational change in the protein that results in the pumping of protons from the cytosol across the bacterial membrane to the extracellular space. The proton concentration gradient thus generated across the membrane is used to synthesize ATP (Chapter 8). In the high-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 of the membrane-spanning segments of bacteriorhodopsin are hydrophobic and interact with the hydrocarbon core of the surrounding lipid bilayer.

Ion channels compose a second large and important family of multipass transmembrane proteins. As revealed by the crystal structure of a resting K+ channel, ion channels are typically tetrameric proteins. Each of the four subunits has a pair of membrane-spanning helices that bundle with helices

▲ FIGURE 5-12 Structure of glycophorin A, a typical singlepass transmembrane protein. (a) Diagram of dimeric glycophorin showing major sequence features and its relation to the membrane. The single 23-residue membrane-spanning a helix in each monomer is composed of amino acids with hydrophobic (uncharged) side chains (red spheres). By binding negatively charged phospholipid head groups, the positively charged arginine and lysine residues (blue spheres) near the cytosolic side of the helix help anchor glycophorin in the membrane. Both the extracellular and the cytosolic domains are rich in charged residues and polar uncharged residues; the extracellular domain is heavily glycosylated, with the carbohydrate side chains (green diamonds) attached to specific serine, threonine, and asparagine residues. (b) Molecular model of the transmembrane domain of dimeric glycophorin corresponding to residues 73-96. The side chains of the a helix in one monomer are shown in red; those in the other monomer, in gray. Residues depicted as space-filling structures participate in intermonomer van der Waals interactions that 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 Figure 7-15). Polar and hydrophobic residues lining the center of the bundle form a channel in the membrane, but as with bac-teriorhodopsin virtually all of the amino acids on the exterior of the membrane-spanning domain are hydrophobic. In many ion channels, external factors (e.g., a ligand, voltage, or mechanical strain) regulate ion flow across the bilayer by reorienting the helices. Details of ion channels and their structures are discussed in Chapter 7.

M FIGURE 5-13 Structural model of bacteriorhodopsin, a multipass transmembrane protein that functions as a photoreceptor in certain bacteria. The seven hydrophobic a helices in bacteriorhodopsin traverse the lipid bilayer. A retinal molecule (red) covalently attached to one helix absorbs light. The large class of G protein-coupled receptors in eukaryotic cells also has seven membrane-spanning a helices; their three-dimensional structure is similar to that of bacteriorhodopsin. [After H. Luecke et al., 1999, J. Mol. Biol. 291:899.]

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