Figure 3–16 an extended structure formed from a series of protein domains. Four fibronectin type 3 domains (see Figure 3–15) from the extracellular matrix molecule fibronectin are illustrated in (A) ribbon and (B) space-filling models. (Adapted from D.J. Leahy, I. Aukhil and H.P. Erickson, Cell 84:155–164, 1996. With permission from Elsevier.)
A second feature of these protein domains that explains their utility is the ease with which they can be integrated into other proteins. Two of the three domains illustrated in Figure 3–15 have their Nand C-terminal ends at opposite poles of the domain. When the DNA encoding such a domain undergoes tandem duplication, which is not unusual in the evolution of genomes (discussed in Chapter 4), the duplicated domains with this “in-line” arrangement can be readily linked in series to form extended structures—either with themselves or with other in-line domains (Figure 3–16). Stiff extended structures composed of a series of domains are especially common in extracellular matrix molecules and in the extracellular portions of cell-surface receptor proteins. Other frequently used domains, including the kringle domain illustrated in Figure 3–15 and the SH2 domain, are of a “plug-in” type, with their Nand C-termini close together. After genomic rearrangements, such domains are usually accommodated as an insertion into a loop region of a second protein.
A comparison of the relative frequency of domain utilization in different eukaryotes reveals that, for many common domains, such as protein kinases, this frequency is similar in organisms as diverse as yeast, plants, worms, flies, and humans. But there are some notable exceptions, such as the Major Histocompatibility Complex (MHC) antigen-recognition domain (see Figure 24–36) that is present in 57 copies in humans, but absent in the other four organisms just mentioned. Domains such as these have specialized functions that are not shared with the other eukaryotes; they are assumed to have been strongly selected for during recent evolution to produce the multiple copies observed. Similarly, the SH2 domain shows an unusual increase in its numbers in higher eukaryotes; such domains might be assumed to be especially useful for multicellularity.
Certain Pairs of Domains Are Found Together in Many Proteins
We can construct a large table displaying domain usage for each organism whose genome sequence is known. For example, the human genome contains the DNA sequences for about 1000 immunoglobulin domains, 500 protein kinase domains, 250 DNA-binding homeodomains, 300 SH3 domains, and 120 SH2 domains. In addition, we find that more than two-thirds of all proteins consist of two or more domains, and that the same pairs of domains occur repeatedly in the same relative arrangement in a protein. Although half of all domain families are common to archaea, bacteria, and eukaryotes, only about 5% of the two-domain combinations are similarly shared. This pattern suggests that most proteins containing especially useful two-domain combinations arose through domain shuffling relatively late in evolution.
The Human Genome Encodes a Complex Set of Proteins, Revealing That Much Remains Unknown
The result of sequencing the human genome has been surprising, because it reveals that our chromosomes contain only about 21,000 protein-coding genes. Based on this number alone, we would appear to be no more complex than the tiny mustard weed, Arabidopsis, and only about 1.3-fold more complex than a nematode worm. The genome sequences also reveal that vertebrates have inherited nearly all of their protein domains from invertebrates—with only 7% of identified human domains being vertebrate-specific.
Each of our proteins is on average more complicated, however (Figure 3–17). Domain shuffling during vertebrate evolution has given rise to many novel
Figure 3–17 Domain structure of a group of evolutionarily related proteins that are thought to have a similar function. In general, there is a tendency for the proteins in more complex organisms, such as humans, to contain additional domains—as is the case for the DNA-binding protein compared here.