Biological Regulation by Protein Phosphorylation
661
Fig. 1
Protein kinases catalyze the
transfer of a phosphate group onto a
speciFc amino acid side chain of a
substrate protein. ATP usually serves as
the phosphate donor, and serine,
threonine, and tyrosine residues serve
as phosphate acceptors. The reversible
phosphorylation of a protein causes a
change in its biological activity.
Phosphoprotein phosphatases remove
the phosphate group allowing the
protein to return to its former functional
state. The relative activities of the
protein kinase and protein phosphatase
generally determine the phosphorylation
state of the protein. (ModiFed from
Scott and Patel, Encyclopedia of Human
Biology (1991) 6; 201–211; reproduced
by permission of Academic Press.)
Protein
Protein
O
P
=
O
O
O
OH
P
i
Protein kinase
Protein phosphatase
ATP
ADP
can also occur at sites distal to the cat-
alytic site and regulate enzyme function
by inducing long-range conformational
changes. Phosphorylation has been shown
to affect the biological properties of pro-
teins by altering their intracellular location,
enhancing their susceptibility to proteoly-
sis, and modulating their ability to interact
with other proteins. Phosphoprotein phos-
phatases remove the phosphate group,
thereby allowing the protein to return to its
previous functional state. Some proteins
become active when dephosphorylated and
are inactivated by phosphorylation. An ex-
ample is glycogen synthase, an enzyme
that catalyzes the conversion of glucose
to glycogen. This enzyme is active in
the dephosphorylated form. When phos-
phorylated by glycogen synthase kinase 3
(GSK3), glycogen synthase becomes in-
active thereby limiting the synthesis of
glycogen. In general, both protein ki-
nases and phosphoprotein phosphatases
are under stringent regulatory control. The
activation state of the relevant kinase and
phosphatase will usually determine when a
protein becomes phosphorylated and how
long it remains phosphorylated.
2
Classifcation and Properties o± Protein
Kinases
Protein kinases share a highly conserved
catalytic domain called the
kinase domain
(also known as the
catalytic core
). The high
conservation of this domain has helped
identify protein kinase genes from the vari-
ous large-scale genome sequencing efforts
of human, yeast (
Saccharomyces cerevisiae
),
fly (
Drosophila melanogaster
), and worm
(
Caenorhabditis elegans
). Over 500 protein
kinase genes have been identiFed in the
human genome, representing about 2%
o
fthehumangenes
.Thek
inasedoma
in
is the third most abundant domain en-
coded in the human genome, with the
immunoglobulin and zinc Fnger domains
being the most prevalent.
More than 170 crystal structures of pro-
tein kinases have been resolved, providing
an insight into the structure and function
of these enzymes. The kinase domain con-
tains two major structural domains named
N- and C-terminal domains (±ig. 2). These
two domains are bridged through a short
linker peptide, around which they rotate in
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