Essential Cell Biology 5th edition

152 CHAPTER 4 Protein Structure and Function
Figure 4−45 The binding of a regulatory
ligand can change the equilibrium
between two protein conformations.
(A) Schematic diagram of a hypothetical,
allosterically regulated enzyme for which a
rise in the concentration of ADP molecules
(red wedges) increases the rate at which
the enzyme catalyzes the oxidation of
sugar molecules (blue hexagons).
(B) Due to thermal motions, the enzyme
will spontaneously interconvert between
the open (inactive) and closed (active)
conformations shown in (A). But when
ADP is absent, only a small fraction of
the enzyme molecules will be present
in the active conformation at any given
time. As illustrated, most remain in the
inactive conformation. (C) Because ADP
can bind to the protein only in its closed,
active conformation, an increase in ADP
concentration locks nearly all of the enzyme
molecules in the active form—an example
of positive regulation. In cells, rising
concentrations of ADP signal a depletion
of ATP reserves; increased oxidation of
sugars—in the presence of ADP—thus
provides more energy for the synthesis of
ATP from ADP.
ADP
INACTIVE
ACTIVE
sugar
(such as
glucose)
positive
regulation
(A) (B) without ADP, 10% active
(C) with ADP, 100% active
altered when the protein changes shape. Each ligand will stabilize the
conformation that it binds to most strongly. Therefore, at high enough
concentrations, a ligand will tend to “switch” the population of proteins
to the conformation that ECB5 it 04.45 favors (Figure 4−45B and C).
Phosphorylation Can Control Protein Activity by Causing
a Conformational Change
Another method that eukaryotic cells use to regulate protein activity
involves attaching a phosphate group covalently to one or more of the
protein’s amino acid side chains. Because each phosphate group carries
two negative charges, the enzyme-catalyzed addition of a phosphate
group can cause a conformational change by, for example, attracting a
cluster of positively charged amino acid side chains from somewhere else
in the same protein. This structural shift can, in turn, affect the binding
of ligands elsewhere on the protein surface, thereby altering the protein’s
activity. Removal of the phosphate group by a second enzyme will return
the protein to its original conformation and restore its initial activity.
Reversible protein phosphorylation controls the activity of many types
of proteins in eukaryotic cells. This form of regulation is used so extensively
that more than one-third of the 10,000 or so proteins in a typical
mammalian cell are phosphorylated at any one time. The addition and
removal of phosphate groups from specific proteins often occur in
response to signals that specify some change in a cell’s state. For example,
the complicated series of events that takes place as a eukaryotic cell
divides is timed largely in this way (discussed in Chapter 18). And many
of the intracellular signaling pathways activated by extracellular signals
depend on a network of protein phosphorylation events (discussed in
Chapter 16).
Protein phosphorylation involves the enzyme-catalyzed transfer of the
terminal phosphate group of ATP to the hydroxyl group on a serine, threonine,
or tyrosine side chain of the protein. This reaction is catalyzed
by a protein kinase. The reverse reaction—removal of the phosphate
group, or dephosphorylation—is catalyzed by a protein phosphatase
(Figure 4−46A). Phosphorylation can either stimulate protein activity or
inhibit it, depending on the protein involved and the site of phosphorylation
(Figure 4−46B). Cells contain hundreds of different protein kinases,
each responsible for phosphorylating a different protein or set of proteins.
Cells also contain a smaller set of different protein phosphatases;
some of these are highly specific and remove phosphate groups from only
one or a few proteins, whereas others act on a broad range of proteins.
The state of phosphorylation of a protein at any moment in time, and thus
ADP