662
Biological Regulation by Protein Phosphorylation
N-terminal domain
Linker
C-terminal domain
Catalytic loop
Fig. 2
Ribbon diagram of the kinase domain of ERK2 (p42 MAPK), a
protein serine–threonine kinase. The four prototypic subdomains are
labeled and color-coded.
response to protein substrate and/or ATP-
binding. Also located in the C-terminal
domain is a short peptide strand called
the
catalytic loop
, which contains an invari-
ant aspartate that is critical for catalysis.
The ATP binds in a deep cleft between
the N- and C-terminal domains that con-
tain a part of the linker region and
the catalytic loop. The protein substrate
binding site is composed of shallow sur-
face depressions, whose structural features
vary among different protein kinases and
thereby influence substrate speciFcity. The
shallow surface depressions do not provide
adequate interaction sites for high afFnity
binding of small molecules. Thus, the vast
majority of small-molecule inhibitors iden-
tiFed so far bind to the ATP binding site.
Protein kinases recognize phosphory-
lation sites within particular amino acid
sequences called
consensus sequences
or
recognition motifs
. Studies using peptide
substrates containing altered amino acid
sequences have revealed the importance of
primary sequence in distinguishing phos-
phorylation sites. ±or example, cAMP-
dependent protein kinase will phospho-
rylate a serine or threonine residue in the
sequence -Arg-Arg-
X
-Ser/Thr-
X
-, where
X
represents any amino acid. Eliminating
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