Essential Cell Biology 5th edition

How Proteins Are Controlled
153
Figure 4−46 Protein phosphorylation is a very common mechanism
for regulating protein activity. Many thousands of proteins in a typical
eukaryotic cell are modified by the covalent addition of one or more
phosphate groups. (A) The general reaction, shown here, entails transfer
of a phosphate group from ATP to an amino acid side chain of the target
protein by a protein kinase. Removal of the phosphate group is catalyzed
by a second enzyme, a protein phosphatase. In this example, the
phosphate is added to a serine side chain; in other cases, the phosphate
is instead linked to the –OH group of a threonine or tyrosine side chain.
(B) Phosphorylation can either increase or decrease the protein’s activity,
depending on the site of phosphorylation and the structure of the protein.
OH
serine
CH
side chain 2
C
ATP
ADP
PROTEIN
KINASE
PROTEIN
PHOSPHATASE
O
O _
P O _
O
CH 2
C
its activity, will depend on the relative activities of the protein kinases
and phosphatases that act on it.
(A)
P
phosphorylated
protein
Phosphorylation can take place in a continuous cycle, in which a phosphate
group is rapidly added to—and rapidly removed from—a particular
side chain. Such phosphorylation cycles allow proteins to switch quickly
from one state to another. The more swiftly the cycle is “turning,” the
faster the concentration of a phosphorylated protein can change in
response to a sudden stimulus. Although keeping the cycle turning costs
energy—because ATP is hydrolyzed with each phosphorylation—many
enzymes in the cell undergo this speedy, cyclic form of regulation.
Covalent Modifications Also Control the Location and
Interaction of Proteins
Phosphorylation can do more than control a protein’s activity; it can
create docking sites where other proteins can bind, thus promoting the
assembly of proteins into larger complexes. For example, when extracellular
signals stimulate a class of cell-surface, transmembrane proteins
called receptor tyrosine kinases, they cause the receptor proteins to phosphorylate
themselves on certain tyrosines. The phosphorylated tyrosines
then serve as docking sites for the binding and activation of a set of
intracellular signaling proteins, which transmits the message to the cell
interior and changes the behavior of the cell (see Figure 16−29).
Phosphorylation is not the only form of covalent modification that can
affect a protein’s function. Many proteins are modified by the addition of
an acetyl group to a lysine side chain, including the histones discussed
in Chapter 5. And the addition of the fatty acid palmitate to a cysteine
side chain drives a protein to associate with cell membranes. Attachment
of ubiquitin, a 76-amino-acid polypeptide, can target a protein for degradation,
as we discuss in Chapter 7. More than 100 types of covalent
modifications can occur in the cell, each playing its own role in regulating
protein function. Each of these modifying groups is enzymatically added
or removed depending on the needs of the cell.
A large number of proteins are modified on more than one amino acid
side chain. The p53 protein, which plays a central part in controlling how
a cell responds to DNA damage and other stresses, can be covalently
modified at 20 sites (Figure 4−47). Because an enormous number of combinations
of these 20 modifications is possible, the protein’s behavior can
in principle be altered in a huge number of ways.
H 2 N
SOME KNOWN MODIFICATIONS OF PROTEIN p53
P
P
P
P
P
P P P P P
phosphate groups
50 amino acids
acetyl groups
Ac Ac
P
U
U
ubiquitin
P
Ac
Ac
P
OFF
ON
(B)
COOH
kinase
P
phosphatase
kinase
P
phosphatase
P
ECB5 e4.42/4.41
P
ON
OFF
Figure 4−47 The modification of
a protein at multiple sites can
control the protein’s behavior. This
diagram shows some of the covalent
modifications that control the activity
and degradation of p53, a protein
of nearly 400 amino acids. p53 is an
important transcription regulator that
regulates a cell’s response to damage
(discussed in Chapter 18). Not all of
these modifications will be present
at the same time. Colors along the
body of the protein represent distinct
protein domains, including one that
binds to DNA (green) and one that
activates gene transcription (pink). All
of the modifications shown are located
within relatively unstructured regions
of the polypeptide chain.