146
Calcium Biochemistry
5.1.1
Calmodulin and its Targets
5.1.1.1
Structural principles of
Calmodulin-target interactions
As pointed out before, calmodulin (CaM)
undergoes
a
profound
conformational
change upon binding of Ca
2
+
to the
different EF-hand loops of the protein. As
a consequence, deep hydrophobic clefts
are built that are a prerequisite for the
interaction with targets. In the absence of
a target, the N-terminal and the C-terminal
halves of CaM behave as independent
structural units in solution that are linked
by a flexible tether. The latter is part of the
seven-turn central helix observed in the
crystal structure of the protein.
CaM binding sequences of different tar-
gets reveal similar properties (see Table 1).
They are composed of short peptides
with an average length of 20 to 30
amino acids that have the propensity to
form a basic amphiphilic
α
-helix. Several
three-dimensional structures of complexes
between calmodulin and target peptides
representing binding domains of different
CaM-dependent kinases, such as skeletal
muscle and smooth muscle myosin light
chain kinase (MLCK), CaM-dependent
protein kinase II, and CaM-dependent
protein kinase kinase, have been solved
by either NMR or X-ray crystallography.
These structures share some common
structural features:
1. Calmodulin, which usually has an ex-
tended, dumbbell-type shape, is col-
lapsed to a globular structure wrapped
around the target peptide
2. The peptide is located in a hydrophobic
channel passing through the center of
the globular molecule
3. Two hydrophobic residues of the bind-
ing peptide spaced by a de±ned number
of residues are essential for the interac-
tion with CaM (see Table 1).
4. The peptides interact with CaM in
an antiparallel manner, that is, the
N-terminal half of CaM binds the C-
terminal part of the peptide and
vice
versa
. Structural examples of some
CaM-target interactions are presented
in Fig. 2 showing the structures of
calmodulin in its Ca
2
+
-bound form and
how it interacts with the CaM binding
domains of the plasma membrane
calcium pump and of MLCK.
An exception to rule (4) was recently
reported by Ikura et al. who solved the
structure of the complex of CaM bound
to the peptide of the binding domain
of CaMKK by NMR. In this complex,
the peptide comprises unusual structural
properties, that is, only the N-terminal
Tab. 1
Aligned sequences of CaM binding Domains of
CaM-dependent Protein Kinases.
skMLCK (M13)
KRR
W
KKNFIAVS
A ANR
F
KKI
smMLCK (R20)
RRK
W
QKTGHAVRA IGR
L
SSM
CAMKI
KSK
W
KQAFNATA
V
VRH
M
RKL
CAMKII
RRK
L
KGAILTTM
L
ATRN
FSA
CAMKIV
RRK
L
KAAVKAVV A SSR
L
GSA
CAMKK
IPS
W
TTVILVKS
MLRK
RS
F
G
Boxed hydrophobic residues represent the critical anchoring
amino acids of the different CaM binding domains.
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