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
