The backbone conformations of elastase and chymotrypsin. Although only those amino acids in the polypeptide chain shaded in green are the same in the two proteins, the two conformations are very similar nearly everywhere. The active site of each enzyme is circled in red; this is where the peptide bonds of the proteins that serve as substrates are bound and cleaved by hydrolysis. The serine proteases derive their name from the amino acid serine, whose side chain is part of the active site of each enzyme and directly participates in the cleavage reaction. The two dots on the right side of the chymotrypsin molecule mark the new ends created when this enzyme cuts its own backbone.
Figure 3–13 a comparison of a class of Dna-binding domains, called homeodomains, in a pair of proteins from two organisms separated by more than a billion years of evolution. (A) A ribbon model of the structure common to both proteins. (B) A trace of the α-carbon positions. The three-dimensional structures shown were determined by x-ray crystallography for the yeast α2 protein (green) and the Drosophila engrailed protein (red). (C) A comparison of amino acid sequences for the region of the proteins shown in (A) and (B). Black dots mark sites with identical amino acids. Orange dots indicate the position of a three-amino-acid insert in the α2 protein. (Adapted from C. Wolberger et al., Cell 67:517–528, 1991. With permission from Elsevier.) protein family has been more highly conserved than has the amino acid sequence. In many cases, the amino acid sequences have diverged so far that we cannot be certain of a family relationship between two proteins without determining their three-dimensional structures. The yeast α2 protein and the Drosophila engrailed protein, for example, are both gene regulatory proteins in the homeodomain family (discussed in Chapter 7). Because they are identical in only 17 of their 60 amino acid residues, their relationship became certain only by comparing their three-dimensional structures (Figure 3–13). Many similar examples show that two proteins with more than 25% identity in their amino acid sequences usually share the same overall structure.
The various members of a large protein family often have distinct functions. Some of the amino acid changes that make family members different were no doubt selected in the course of evolution because they resulted in useful changes in biological activity, giving the individual family members the different functional properties they have today. But many other amino acid changes are effectively “neutral,” having neither a beneficial nor a damaging effect on the basic structure and function of the protein. In addition, since mutation is a random process, there must also have been many deleterious changes that altered the three-dimensional structure of these proteins sufficiently to harm them. Such faulty proteins would have been lost whenever the individual organisms making them were at enough of a disadvantage to be eliminated by natural selection.
Protein families are readily recognized when the genome of any organism is sequenced; for example, the determination of the DNA sequence for the entire human genome has revealed that we contain about 21,000 protein-coding genes. (Note, however, that as a result of alternative RNA splicing, human cells can produce much more than 21,000 different proteins, as will be explained in Chapter 6.) Through sequence comparisons, we can assign the products of at least 40% of our protein-coding genes to known protein structures, belonging to more than 500 different protein families. Most of the proteins in each family have evolved to perform somewhat different functions, as for the enzymes elastase and chymotrypsin illustrated previously in Figure 3–12. As explained in Chapter 1 (see Figure 1–21), these are sometimes called paralogs to distinguish them from the many corresponding proteins in different organisms (orthologs, such as mouse and human elastase).