Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

122 Chapter 3: Proteins
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 N- and 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 N- and 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
(A)
Znf
Ep1
Ep1
PHD
PHD
yeast
worm
human
(B)
MBoC6 m3.17/3.16
PHD
PHD
Ep2
Ep2
Ep1 PHD PHD Ep2 Br
BMB
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.
MBoC6 m3.19/3.17
Br