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

158 Chapter 3: Proteins
modified with a different type of polyubiquitin chain. These modifications have
different functional consequences for the protein that is targeted (Figure 3–69B).
Related structures are created when a different member of the ubiquitin family,
such as SUMO (small ubiquitin-related modifier), is covalently attached to a
lysine side chain of target proteins. Not surprisingly, all such modifications are
reversible. Cells contain sets of ubiquitylating and deubiquitylating (and sumoylating
and desumoylating) enzymes that manipulate these covalent adducts,
thereby playing roles analogous to the protein kinases and phosphatases that add
and remove phosphates from protein side chains.
An Elaborate Ubiquitin-Conjugating System Is Used to Mark
Proteins
How do cells select target proteins for ubiquitin addition? As an initial step, the
carboxyl end of ubiquitin needs to be activated. This activation is accomplished
when a protein called a ubiquitin-activating enzyme (E1) uses ATP hydrolysis
energy to attach ubiquitin to itself through a high-energy covalent bond (a thioester).
E1 then passes this activated ubiquitin to one of a set of ubiquitin-conjugating
(E2) enzymes, each of which acts in conjunction with a set of accessory
(E3) proteins called ubiquitin ligases. There are roughly 30 structurally similar
but distinct E2 enzymes in mammals, and hundreds of different E3 proteins that
form complexes with specific E2 enzymes.
Figure 3–70 illustrates the process used to mark proteins for proteasomal
degradation. [Similar mechanisms are used to attach ubiquitin (and SUMO) to
other types of target proteins.] Here, the ubiquitin ligase binds to specific degradation
signals, called degrons, in protein substrates, thereby helping E2 to form a
polyubiquitin chain linked to a lysine of the substrate protein. This polyubiquitin
chain on a target protein will then be recognized by a specific receptor in the
proteasome, causing the target protein to be destroyed. Distinct ubiquitin ligases
recognize different degradation signals, thereby targeting distinct subsets of
intracellular proteins for destruction, often in response to specific signals (see
Figure 6–86).
NH 2
COOH
switch
helix
P
P
Figure 3–67 The structure of the Ras
protein in its GTP-bound form. This
monomeric GTPase illustrates the structure
of a GTP-binding domain, which is present
in a large family of GTP-binding proteins.
The red regions change their conformation
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when the GTP molecule is hydrolyzed
to GDP and inorganic phosphate by the
protein; the GDP remains bound to the
protein, while the inorganic phosphate is
released. The special role of the “switch
helix” in proteins related to Ras is
explained in the text (see Figure 3–72
and Movie 15.7).
P
GTP
site of GTP
hydrolysis
SIGNAL IN
SIGNAL IN
PROTEIN
KINASE
ATP
GEF
GDP
OFF
GDP
OFF
ADP
ON
P i
PROTEIN
PHOSPHATASE
GTP
ON
GAP
P i
P
SIGNAL OUT
GTP
SIGNAL OUT
SIGNALING BY PHOSPHORYLATED PROTEIN
SIGNALING BY GTP-BINDING PROTEIN
Figure 3–68 A comparison of two major intracellular signaling mechanisms in eukaryotic
cells. In both cases, a signaling protein is activated by the addition of a phosphate group and
inactivated by the removal of this phosphate. Note that the addition of a phosphate to a protein
can also be inhibitory. (Adapted from E.R. Kantrowitz and W.N. Lipscomb, Trends Biochem. Sci.
15:53–59, 1990.)
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