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

126 Chapter 3: Proteins
produce a rubberlike, elastic meshwork that can be reversibly pulled from one
conformation to another, as illustrated in Figure 3–23B. The elastic fibers that
result enable skin and other tissues, such as arteries and lungs, to stretch and
recoil without tearing.
Intrinsically disordered regions of proteins are frequent in nature, and they
have important functions in the interior of cells. As we have already seen, proteins
often have loops of polypeptide chain that protrude from the core region of a protein
domain to bind other molecules. Some of these loops remain largely unstructured
until they bind to a target molecule, adopting a specific folded conformation
only when this other molecule is bound. Many proteins were also known to
have intrinsically disordered tails at one or the other end of a structured domain
(see, for example, the histones in Figure 4–24). But the extent of such disordered
structure only became clear when genomes were sequenced. This allowed bioinformatic
methods to be used to analyze the amino acid sequences that genes
encode, searching for disordered regions based on their unusually low hydrophobicity
and relatively high net charge. Combining these results with other data, it is
now thought that perhaps a quarter of all eukaryotic proteins can adopt structures
that are mostly disordered, fluctuating rapidly between many different conformations.
Many such intrinsically disordered regions contain repeated sequences of
amino acids. What do these disordered regions do?
Some known functions are illustrated in Figure 3–24. One predominant function
is to form specific binding sites for other protein molecules that are of high
specificity, but readily altered by protein phosphorylation, protein dephosphorylation,
or any of the other covalent modifications that are triggered by cell signaling
events (Figure 3–24A and B). We shall see, for example, that the eukaryotic
RNA polymerase enzyme that produces mRNAs contains a long, unstructured
C-terminal tail that is covalently modified as its RNA synthesis proceeds, thereby
attracting specific other proteins to the transcription complex at different times
(see Figure 6–22). And this unstructured tail interacts with a different type of low
complexity domain when the RNA polymerase is recruited to the specific sites on
the DNA where it begins synthesis.
As illustrated in Figure 3–24C, an unstructured region can also serve as a
“tether” to hold two protein domains in close proximity to facilitate their interaction.
For example, it is this tethering function that allows substrates to move
between active sites in large multienzyme complexes (see Figure 3–54). A similar
tethering function allows large scaffold proteins with multiple protein-binding
sites to concentrate sets of interacting proteins, both increasing reaction rates and
confining their reaction to a particular site in a cell (see Figure 3–78).
Like elastin, other proteins have a function that directly requires that they
remain largely unstructured. Thus, large numbers of disordered protein chains
in close proximity can create micro-regions of gel-like consistency inside the cell
that restrict diffusion. For example, the abundant nucleoporins that coat the inner
surface of the nuclear pore complex form a random coil meshwork (Figure 3–24)
that is critical for selective nuclear transport (see Figure 12–8).
(A)
+
BINDING
(B)
P
P
P
P
P
SIGNALING
P
(C)
TETHERING
(D)
DIFFUSION BARRIER
Figure 3–24 Some important functions
for intrinsically disordered protein
sequences. (A) Unstructured regions
of polypeptide chain often form binding
sites for other proteins. Although these
binding events are of high specificity,
they are often of low affinity due to the
free-energy cost of folding the normally
unfolded partner (and they are thus readily
reversible). (B) Unstructured regions can
be easily modified covalently to change
their binding preferences, and they are
therefore frequently involved in cell signaling
processes. In this schematic, multiple sites
of protein phosphorylation are indicated.
(C) Unstructured regions frequently create
“tethers” that hold interacting protein
domains in close proximity. (D) A dense
network of unstructured proteins can form
a diffusion barrier, as the nucleoporins do
for the nuclear pore.