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CaMKK-Ca2+-CALMODULIN
COMPLEX
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CaMKK
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| The calmodulin binding domain
of Calmodulin-dependent
kinase kinase (CaMKK) is unusual because it
binds in the reverse orientation from any other peptides
whose structures in complex with calmodulin have been
solved so far. Three other structures that have been studied
to this date (smooth muscle myosin light chain kinase
(smMLCK by Meador et al, 1992),
skeletal muscle myosin light chain kinase (skMLCK by Ikura
et al, 1992), calmodulin-dependent kinase II (CaMKII
by Meador et al, 1993)) all
show that peptides bind to calmodulin with the N-terminus
of the peptide in the C-terminal domain of calmodulin.
CaMKK, in contrast, binds in the reverse orientation such
that the N-terminus of the peptide binds to the N-terminal domain
of calmodulin. |
Figure 1
PDB 1CKK
Picture created with RasMac v2.6 |
| In
Figure 1, white balls represent calcium ions. Residues
colored in red, orange and violet are the key anchor residues
as identified by Osawa et al
(1999): Trp444, Met453 and Phe459 respectively. As
you can see, the anchor residues make numerous contacts
in the hydrophobic pockets in the calmodulin. For bigger
picture, click here or click
on the picture above. |
Figure 2
Picture created with RasMac v2.6
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Osawa
et al (1999) noted that C-terminal domain of calmodulin
is more negatively charged than the N-terminal domain.
They suggest that the charge distribution on calmodulin
may affect the binding orientation of the peptides. This
is shown in three groups of this database: basic
1-8-14 group, basic
1-5-10 group, and the 1-16
group.
The basic 1-8-14 and basic 1-5-10 groups both have
three basic residues immediately prior to the first hydrophobic
anchor residue near the N-terminus; CaMKK group has three
basic residues near the C-terminus of the peptide. Basic
1-8-14 and basic 1-5-10 peptides bind in the opposite
orientation from the CaMKK peptides.
In Figure 2, three tandem basic residues near the last
bulky hydrophobic anchor (Arg455, Lys456, Arg457) is shown
in purple. For larger picture, click here
or click on the picture. |
Another
feature that Osawa et al (1999) noted was that C-terminal
domain of calmodulin was able to accomodate larger volume
than the N-terminal domain. Osawa et al (1999) defined
the term Channel Outlet as the region in the domain through
which peptides go. Basically, channel outlet (CO) is the
hole in the domain. CO-1 is in the N-terminal domain,
whereas CO-2 is in th C-terminal domain. Osawa et al showed
that CO-2 is indeed larger in the solution structure,
and thus able to accomodate larger volume. Here, the peptide
doubles back on itself, and yet, calmodulin is able to
bind all.
In Figure 3, one can see that the CO-2 at the bottom is
indeed larger than CO-1 at the top. For larger picture,
click here or click on
the picture. |
Figure 3
Picture created with RasMac v2.6
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| As
you can see, calmodulin shows unusual flexibility and
diversity in binding peptides. Not only can it bind to
many different hydrophobic residues in its binding pocket,
but also to many differently shaped peptides. It is probable
that more we study the structure, more diversity we will
find. |
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