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

156 Chapter 3: Proteins
NH 2
fatty
acid
SH3 SH2 kinase domains
500 amino acids
COOH
Figure 3–63 The domain structure of the
Src family of protein kinases, mapped
along the amino acid sequence. For the
three-dimensional structure of Src, see
Figure 3–13.
amino acids come two peptide-binding domains, a Src homology 3 (SH3) domain
and an SH2 domain, followed by the kinase catalytic domain (Figure 3–63). These
kinases normally exist in an inactive conformation, in which a phosphorylated
tyrosine near the C-terminus MBoC6 is bound m3.68/3.59 to the SH2 domain, and the SH3 domain
is bound to an internal peptide in a way that distorts the active site of the enzyme
and helps to render it inactive.
As shown in Figure 3–64, turning the kinase on involves at least two specific
inputs: removal of the C-terminal phosphate and the binding of the SH3 domain
by a specific activating protein. In this way, the activation of the Src kinase signals
the completion of a particular set of separate upstream events (Figure 3–65).
Thus, the Src family of protein kinases serves as specific signal integrators, contributing
to the web of information-processing events that enable the cell to compute
useful responses to a complex set of different conditions.
Proteins That Bind and Hydrolyze GTP Are Ubiquitous Cell
Regulators
We have described how the addition or removal of phosphate groups on a protein
can be used by a cell to control the protein’s activity. In the example just discussed,
a kinase transfers a phosphate from an ATP molecule to an amino acid side chain
of a target protein. Eukaryotic cells also have another way to control protein activity
by phosphate addition and removal. In this case, the phosphate is not attached
directly to the protein; instead, it is a part of the guanine nucleotide GTP, which
binds very tightly to a class of proteins known as GTP-binding proteins. In general,
proteins regulated in this way are in their active conformations with GTP bound.
The loss of a phosphate group occurs when the bound GTP is hydrolyzed to GDP
in a reaction catalyzed by the protein itself, and in its GDP-bound state the protein
is inactive. In this way, GTP-binding proteins act as on–off switches whose activity
is determined by the presence or absence of an additional phosphate on a bound
GDP molecule (Figure 3–66).
GTP-binding proteins (also called GTPases because of the GTP hydrolysis
they catalyze) comprise a large family of proteins that all contain variations on
the same GTP-binding globular domain. When a tightly bound GTP is hydrolyzed
by the GTP-binding protein to GDP, this domain undergoes a conformational
activating ligand
SH3
kinase domain
tyrosine
P
P
active
kinase
SH2
P
OFF
P i
PHOSPHATE
REMOVAL
LOOSENS
STRUCTURE
ACTIVATING
LIGAND BINDS
TO SH3 DOMAIN
KINASE CAN NOW
PHOSPHORYLATE
TYROSINE TO
SELF-ACTIVATE
ON
P
Figure 3–64 The activation of a Src-type protein kinase by two sequential events. As described in the text, the requirement for multiple
upstream events to trigger these processes allows the kinase to serve as a signal integrator (Movie 3.11). (Adapted from S.C. Harrison et al., Cell
112:737–740, 2003. With permission from Elsevier.)