310
Anthrax (Bacillus anthracis), Molecular Biology of
pulmonary
edema
and
tissue
swelling
that are seen with anthrax infections. LF,
on the other hand, appears to alter the
production of cytokines by macrophages
and to induce macrophage lysis. It is
a
zinc-dependent
metalloprotease
that
cleaves MAP kinase kinases, leading to
apoptosis of the cells through inhibition
of
an
antiapoptotic
signaling
pathway
that involves p38 MAP kinase. LF gets
its
ominous
name
from
the
fact
that
coinjection of PA and LF, even in the
absence of any
B. anthracis
,i
ssu
c
i
en
t
to kill an animal.
Briefly,
the
intoxication
process,
as
we
currently
understand
it,
occurs
as
follows (Fig. 1): PA binds to a ubiquitous
receptor,
named
anthrax
toxin
receptor
(ATR),
on
mammalian
cells.
A
20-kD
amino-terminal piece of PA is then cleaved
off the protein by a furin-like protease,
leaving
the
remaining
63-kD
carboxy-
terminal portion of PA (PA63) bound to
the receptor. This proteolysis, also called
nicking
,
facilitates
the
organization
of
PA63 into a seven-membered ring-shaped
structure, reveals the binding sites for EF
and LF, and stimulates endocytosis of the
PA-LF and PA-EF complexes. The toxin
complexes are
traf±cked
to
endosomal
compartments, wherein low pH triggers
the PA63 ring to insert into the endosomal
membranes as a protein channel. Through
a mechanism that involves unfolding of
EF and LF, the PA63 channel delivers its
ligands to the cytosol of the intoxicated
cells, where they exert their enzymatic
effects.
Protective antigen (PA)
PA63
Anthrax toxin receptor
Lethal factor (LF)
Edema factor (EF)
1.
2.
3.
4.
5.
6.
H+
cAMP
Cleavage of
MAP KK
Fig. 1
Cellular intoxication cycle for anthrax.
Step 1. PA binds to the anthrax toxin receptor.
Step 2. PA is nicked, removing a 20-kD
amino-terminal portion of the protein and
leaving PA63 bound to the receptor. Step 3.
Seven PA63 molecules come together to form a
ring-shaped heptamer. Step 4. The PA63
heptamer binds EF or LF. Step 5. The toxin
complex is endocytosed. Step 6. In response to a
drop in pH in the endosomal compartment, the
PA63 heptamer forms a membrane channel that
mediates the translocation of EF and LF to the
cytosol of cells, where they exert their enzymatic
effects.
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