350
Cell Junctions, Structure, Function, and Regulation
and formation of a mature cell–cell junc-
tion requires the following steps involving
cadherins: (1) the binding of one cadherin
to a second cadherin on the same cell,
referred to as cis-dimer formation; (2) the
binding of a cadherin on one cell to a
cadherin on an adjacent cell, referred to
as trans-dimer formation; (3) the forma-
tion of lateral complexes or clusters; and
(4) the attachment of these complexes to
the cytoskeleton to enhance the strength
of the cell–cell attachment. The Frst two
steps are mediated by the extracellular do-
main, whereas the last two steps occur
through domains on the cytoplasmic tail.
2.3.1
Extracellular Domain: Cis- and
Trans-cadherin Dimerization
The extracellular domain mediates cad-
herin–cadherin binding. The extracellular
domain consists of Fve cadherin domains
that form a rigid, rodlike structure through
the binding of three calcium ions to the
intervening sequence located at the base
of each domain as shown in ±ig. 10. Lat-
eral cis-dimerization is the binding of
two adjacent cadherins within the plasma
membrane of one cell and is mediated by
the interaction of the EC-1 and EC-2 re-
gions of two cadherin molecules (±ig. 11).
This process is thought to require the Trp2
and the hydrophobic pocket created by the
HAV region on the EC-1domain. Indeed,
crystallographic data has shown two pos-
sible scenarios for how these two peptide
regions interact to establish the forma-
tion of a cadherin cis-dimer. In the Frst
model, the Trp2 on one cadherin inserts
into the hydrophobic pocket created by the
HAVreg
iononanad
jacen
tcadher
in
.In
the second model, the Trp2 inserts into
thehydrophob
icpocke
tonthesameEC
-
1 domain resulting in a change in the
conformation of the surrounding amino
acids, which allows interaction with the
EC-1 domain on an adjacent cadherin.
Cadherin
monomer
Cis-
dimer
Cluster
Trans-
dimer
Actin
associated
v
p120
a
-catenin
b
-catenin or
plakoglobin
Fig. 11
Formation of cadherin-mediated cell–cell junction. Cadherin monomers
±rst form cis-dimers through the interaction of the ±rst two cadherin repeats. This
is followed by formation of trans-dimers through the interaction of cadherin
cis-dimers on adjacent cells. The trans-dimers then cluster, increasing the strength
of cell–cell adhesion. The adhesion strength is increased further by the attachment
of the cadherin–catenin complex to the actin cytoskeleton. (See text for details).
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