344
Cell Junctions, Structure, Function, and Regulation
is another transmembrane protein that
functions at hemidesmosomes. BP180 has
a collagenous extracellular domain; its
intracellular domain binds to the
β
4
cy-
toplasmic domain.
The physiological importance of hemi-
desmosomal components is clear from
studies of inherited human skin blister-
ing disorders. In humans, loss of
α
6
β
4
expression or laminin 5 expression causes
a form of epidermolysis bullosa (EB). Pa-
tients with this disorder have very fragile
skin, which is prone to extensive blistering
due to a lack of normal hemidesmosomes.
The adhesion of other epithelia is fragile as
well, affecting organ function such as the
intestines. Most patients suffering from
this disorder survive only several months
after birth at most. Mutations in the BP180
gene cause a less severe form of EB. An-
other form of EB results from mutations
in the plectin gene; this form of EB is
associated with muscular dystrophy indi-
cating the importance of plectin function
in other tissues.
Mice with null mutations in genes
encoding hemidesmosomal components
have similar phenotypes to those described
for the corresponding human hereditary
disorder. These null mice have been use-
ful animal models for these diseases,
providing important insights into the func-
tions of hemidesmosome components.
For example, the skin of plectin-null mice
showed a reduced number of hemidesmo-
somes, and the hemidesmosomes present
had fewer associated keratin ±laments
and exhibited reduced mechanical stabil-
ity. Thus, plectin is not strictly required
for the association of hemidesmosomes
with keratin ±laments. This is not true
for BP230. Targeted deletion of BP230 in
mice also results in a skin blistering phe-
notype. The number of hemidesmosomes
present in the skin of BP230-null mice
was similar to wild-type animals; however,
the hemidesmosomes in BP230-null mice
were not associated with keratin ±laments.
Thus, BP230 plays an essential role in
connecting
α
6
β
4
to keratin ±laments at
hemidesmosomes
in vivo
.
1.5.1
Assembly of Hemidesmosomes
Biochemical and molecular genetic ap-
proaches have been used to characterize
protein interactions with the
β
4
cytoplas-
mic domain and among the components
of the hemidesmosome. Using these ap-
proaches, the
β
4
cytoplasmic domain has
been shown to bind directly to plectin,
BP230 and the cytoplasmic domain of
BP180. Other studies have shown that
BP180 binds to plectin and BP230. The
β
4
cytoplasmic domain has also been shown
to associate with itself; the C-terminal re-
gion of the
β
4
cytoplasmic domain binds
to a site more toward the N-terminal that
overlaps the binding site for plectin. This
β
4
tail-
β
4
-tail interaction could potentially
occur either intramolecularly or inter-
molecularly, and it has been suggested that
the binding of plectin to the
β
4
tail disrupts
this interaction. The importance of indi-
vidual interactions between the various
hemidesmosomal components has been
examined by testing the effect of express-
ing recombinant forms of these proteins,
containing mutations that inhibit speci±c
protein–protein interactions, on the for-
mation of hemidesmosome-like structures
on the basal cell surface of cultured epithe-
lial cells. Emerging evidence from these
types of studies suggests that the assembly
of hemidesmosomes occurs by a stepwise
process. An early step is the binding of
plectin to the
β
4
cytoplasmic domain. The
next step is the recruitment of BP180,
which requires the interaction of BP180
with both
β
4
and plectin, as well as the as-
sociation of plectin with the
β
4
cytoplasmic
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