Figure 3–10 a protein formed from multiple domains. In the Src protein shown, a C-terminal domain with two lobes (yellow and orange) forms a protein kinase enzyme, while the SH2 and SH3 domains perform regulatory functions. (A) A ribbon model, with ATP substrate in red. (B) A space-filling model, with ATP substrate in red. Note that the site that binds ATP is positioned at the interface of the two lobes that form the kinase. The structure of the SH2 domain was illustrated in Figure 3–6. (PDB code: 2SRC.)
Figure 3–11 Ribbon models of three different protein domains. (A) Cytochrome b562, a single-domain protein involved in electron transport in mitochondria. This protein is composed almost entirely of  α helices. (B) The NAD-binding domain of the enzyme lactic dehydrogenase, which is composed of a mixture of α helices and parallel β sheets. (C) The variable domain of an immunoglobulin (antibody) light chain, composed of a sandwich of two antiparallel β sheets. In these examples, the α helices are shown in green, while strands organized as β sheets are denoted by red arrows. Note how the polypeptide chain generally traverses back and forth across the entire domain, making sharp turns only at the protein surface (Movie 3.5). It is the protruding loop regions (yellow) that often form the binding sites for other molecules. (Adapted from drawings courtesy of Jane Richardson.) than one in a billion. And yet the majority of proteins present in cells do adopt unique and stable conformations. How is this possible? The answer lies in natural selection. A protein with an unpredictably variable structure and biochemical activity is unlikely to help the survival of a cell that contains it. Such proteins would therefore have been eliminated by natural selection through the enormously long trial-and-error process that underlies biological evolution.
Because evolution has selected for protein function in living organisms, the amino acid sequence of most present-day proteins is such that a single conformation is stable. In addition, this conformation has its chemical properties finely tuned to enable the protein to perform a particular catalytic or structural function in the cell. Proteins are so precisely built that the change of even a few atoms in one amino acid can sometimes disrupt the structure of the whole molecule so severely that all function is lost. And, as discussed later in this chapter, when certain rare protein misfolding accidents occur, the results can be disastrous for the organisms that contain them.
Once a protein had evolved that folded up into a stable conformation with useful properties, its structure could be modified during evolution to enable it to perform new functions. This process has been greatly accelerated by genetic mechanisms that occasionally duplicate genes, allowing one gene copy to evolve independently to perform a new function (discussed in Chapter 4). This type of event has occurred very often in the past; as a result, many present-day proteins can be grouped into protein families, each family member having an amino acid sequence and a three-dimensional conformation that resemble those of the other family members.
Consider, for example, the serine proteases, a large family of protein-cleaving (proteolytic) enzymes that includes the digestive enzymes chymotrypsin, trypsin, and elastase, and several proteases involved in blood clotting. When the protease portions of any two of these enzymes are compared, parts of their amino acid sequences are found to match. The similarity of their three-dimensional conformations is even more striking: most of the detailed twists and turns in their polypeptide chains, which are several hundred amino acids long, are virtually identical (Figure 3–12). The many different serine proteases nevertheless have distinct enzymatic activities, each cleaving different proteins or the peptide bonds between different types of amino acids. Each therefore performs a distinct function in an organism.
The story we have told for the serine proteases could be repeated for hundreds of other protein families. In general, the structure of the different members of a
Figure 3–12 a comparison of the conformations of two serine proteases.