138
Calcium Biochemistry
protein–protein interactions owing to con-
formational changes of the Ca
2
+
receptors.
2
Ca
2
+
Ligation
Ca
2
+
ligation usually occurs via carboxy-
lates (mono- or bidentate) or neutral
oxygen donors since the calcium ion
overwhelmingly prefers oxygen as donor
groups of ligands. Owing to the great
flexibility of calcium in coordination (co-
ordination numbers usually 6–8, but up
to 12 are possible) and a largely irregu-
lar geometry, both in bond length and in
bond angles, calcium has a superior bind-
ing property to proteins as compared to
Mg
2
+
, which requires a Fxed geometry
of an octahedron with six coordinating
oxygen atoms and a Fxed ionic bond
distance due to the smaller ionic radius
(0.64
˚
A) as compared to 0.97
˚
Aofcalcium.
This difference in flexibility of complexa-
tion geometry permits calcium a greater
versatility in coordinating ligands, lead-
ing to a higher exchange rate. This is
reflected in a three-orders-of-magnitude
difference in dehydration rate between the
two ions, which makes Ca
2
+
much more
suitable as a signal-transducing factor, es-
pec
ia
l
lyinthep
resenceo
fah
ighexcess
of Mg
2
+
, the concentration of which is in
the mM range on both sides of the cellular
membrane.
3
Calcium in the Extracellular Space
It was stated in the introduction that
calcium in the EC± is tightly controlled
to maintain its concentration in a range
of 2 to 5 mM. One of the important
functions of Ca
2
+
in the EC± is to stabilize
the structure of proteins and to mediate
cell–cell or cell–matrix interactions. As
a
consequence,
there
are
a
number
of important extracellular processes that
require calcium, such as blood clotting,
complement activation, or interaction of
cell-surface receptors with their ligands
(e.g. Notch signaling). One important
difference in comparing the Ca
2
+
binding
sites
of
extracellular
and
intracellular
proteins (e.g. E±-hand proteins, see below)
is the spatial arrangement of the ligating
groups. As it will be discussed in detail
below, the intracellular Ca
2
+
binding
proteins show a sequential arrangement
of their ligating residues in contrast to
the extracellular proteins in which these
ligands are usually located at distant
positions in the amino acid sequence (e.g.
α
-lactalbumin). Therefore, those proteins
have a preformed cavity of Ca
2
+
binding
sites
with
a
relative
high
degree
of
rigidity with the consequence that the
on-rate for Ca
2
+
binding is fairly slow.
Since, on the other hand, the off-rate
is relatively fast, the afFnity of Ca
2
+
for the extracellular proteins is usually
low.
However,
owing
to
the
relative
high concentration of Ca
2
+
in the EC±,
these proteins occur in their Ca
2
+
bound
form and are therefore protected against
proteolytic cleavage.
Another important function of Ca
2
+
in
the extracellular space is in mediating
cell–cell adhesion. Essential for these cel-
lular contacts are proteins called
adherins
.
These transmembrane glycoproteins re-
quire calcium for their cell-binding activity.
One of the best-studied molecules is uvo-
morulin or E-cadherin. The extracellular
part of this protein is largely composed of
three repeating domains, each containing
two putative Ca
2
+
binding sites different
from the later-described E±-hand binding
previous page 812 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 814 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off