The transmembrane α helices of many single-pass membrane proteins do not contribute to the folding of the protein domains on either side of the membrane. As a consequence, it is often possible to engineer cells to produce just the cytosolic or extracellular domains of these proteins as water-soluble molecules. This approach has been invaluable for studying the structure and function of these domains, especially the domains of transmembrane receptor proteins (discussed in Chapter 15). A transmembrane α helix, even in a single-pass membrane protein, however, often does more than just anchor the protein to the lipid bilayer. Many single-pass membrane proteins form homoor heterodimers that are held together by noncovalent, but strong and highly specific, interactions between the two transmembrane α helices; the sequence of the hydrophobic amino acids of these helices contains the information that directs the protein–protein interaction.
Similarly, the transmembrane α helices in multipass membrane proteins occupy specific positions in the folded protein structure that are determined by interactions between the neighboring helices. These interactions are crucial for the structure and function of the many channels and transporters that move molecules across cell membranes.
In these proteins, neighboring transmembrane helices in the folded structure of the protein shield many of the other transmembrane helices from the membrane lipids. Why, then, are these shielded helices nevertheless composed primarily of hydrophobic amino acids? The answer lies in the way in which multi-pass proteins are integrated into the membrane during their biosynthesis. As we discuss in Chapter 12, transmembrane α helices are inserted into the lipid bilayer sequentially by a protein translocator. After leaving the translocator, each helix is transiently surrounded by lipids, which requires that the helix be hydrophobic. It is only as the protein folds up into its final structure that contacts are made between adjacent helices, and protein–protein contacts replace some of the protein–lipid contacts (Figure 10–22).
Multipass membrane proteins that have their transmembrane segments arranged as β barrels rather than as α helices are comparatively rigid and therefore tend to form crystals readily when isolated. Thus, some of them were among the first
Figure 10–21 Two short α helices in the aquaporin water channel, each of which spans only halfway through the lipid bilayer. In the plasma membrane, four monomers, one of which is shown here, form a tetramer. each monomer has a hydrophilic pore at its center, which allows water molecules to cross the membrane  in single file (see Figure 11–20 and  Movie 11.6). the two short colored helices are buried at an interface formed by protein–protein interactions. the mechanism by which the channel allows the passage of water molecules is discussed in more detail in chapter 11.
multipass membrane protein structures to be determined by x-ray crystallography. The number of β strands in a β barrel varies widely, from as few as 8 strands to as many as 22 (Figure 10–23).
β-barrel proteins are abundant in the outer membranes of bacteria, mitochondria, and chloroplasts. Some are pore-forming proteins, which create water-filled channels that allow selected small hydrophilic molecules to cross the membrane. The porins are well-studied examples (example 3 in Figure 10–23C). Many porin barrels are formed from a 16-strand, antiparallel β sheet rolled up into a cylindrical structure. Polar amino acid side chains line the aqueous channel on the inside, while nonpolar side chains project from the outside of the barrel to interact with the hydrophobic core of the lipid bilayer. Loops of the polypeptide chain often protrude into the lumen of the channel, narrowing it so that only certain solutes can pass. Some porins are therefore highly selective: maltoporin, for example, preferentially allows maltose and maltose oligomers to cross the outer membrane of E. coli.