358
Cell Junctions, Structure, Function, and Regulation
is similar to that of type I/II cadherins,
although major differences exist in the
sequences of the Fve cadherin repeats.
The EC1 domain has the well-conserved
tryptophan as its second amino acid and
the surrounding AA sequence (10 mer) for
each family is well conserved. The desmo-
somal cadherins also posses a CAR site
with a central alanine. The surrounding
AA differ from those in classical cad-
herins, but again are conserved within
the desmogleins (Dsg1 R-A-L, Dsg2 Y-
A-L, Dsg3 R-A-L) and the desmocollins
(Dsc1a Y-A-T, Dsc2a ±AT, Dsc3a Y-A-S).
The CAR site for Dsg/Dsc has been shown
to play a role in the trans-adhesion of
the desmosomal cadherins; however, as
with the type I and II cadherins, there
is confusion on whether the desmosomal
cadherins bind in a strict homophilic or
heterophilic manner.
To determine the manner by which these
two cadherin families mediate cell–cell
adhesion, Dsg or Dsc were expressed
in Fbroblasts that do not express en-
dogenous cadherins. These early studies
demonstrated that the expression of a
single desmosomal cadherin would not
support cell–cell adhesion, but the expres-
sion of certain Dsg/Dsc pairs resulted in
the formation of cell aggregates. These
studies also demonstrated that in addi-
tion to requiring speciFc Dsg/Dsc pairs,
speciFc cytoplasmic proteins must also
be expressed in order to achieve strong
cell–cell adhesion. Interestingly, the addi-
tion of CAR peptides homologous to either
Dsg or Dsc of the Dsg/Dsc pairs was able to
prevent cell–cell adhesion suggesting that
Dsg/Dsc bound in a heterophilic manner.
Coimmunoprecipitation of Dsc and Dsg
further supported the concept that these
cadherins bind in a heterophilic manner.
However, more recent studies have indi-
cated that CAR peptides homologous to
both the Dsg and the Dsc are required
in order to inhibit epithelial morphogen-
esis in tissues expressing Dsg2 and Dsc2,
or Dsg3 and Dsc3, suggesting that ho-
mophilic interactions are involved in the
in vivo
function of desmosome cadherins
during epithelial morphogenesis. Thus,
current evidence suggests that a com-
bination of heterophilic and homophilic
interactions may participate in cell–cell
adhesion at desmosomes.
2.4.2
Cytoplasmic Tail, Plaque Proteins,
and Attachment to the Cytoskeleton
The cytoplasmic tails of Dsg and Dsc
exhibit distinct structural features. The
cytoplasmic tail of Dsc is much shorter
than that of Dsg and has two forms
as a result of alternative splicing. The
‘‘a’’
form
has
a
CBD
that
binds
to
plakoglobin but not to
β
-catenin. The
CBD is replaced in the ‘‘b’’ form of
the cytoplasmic tail with an insertion of
11 amino acids not found in the ‘‘a’’
form resulting in the inability of the ‘‘b’’
form to bind to plakoglobin. Although
Dsc-b does not bind plakoglobin, this
desmosomal cadherin can still link to the
cytoskeleton, as it can bind to desmoplakin
(DP) and plakophilin-3, two proteins that
also link to intermediate Flaments. As
in Dsc, the cytoplasmic domain of Dsg
contains a CBD that binds to plakoglobin
but not to
β
-catenin. This is followed by
a proline-rich linking region, a repeated
unit domain (RUD), and a terminal glycine
rich domain (DTD). The cytoplasmic tail
of Dsg does not bind directly to DP.
Interestingly, the cytoplasmic regions of
Dsc and Dsg behave differently when
expressed as recombinant proteins lacking
the extracellular domain. Indeed, deletion
mutants containing only the cytoplasmic
domain of Dsc-a can recruit DP and
intermediate
Flaments
to
the
plasma
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