By Heather Rock Woods
X-ray images taken at SSRL have revealed how anthrax
hijacks important cell machinery to enter and destroy human cells. The
results give a clearer picture of how anthrax works and bring researchers
closer to developing a therapy against anthrax infection as well as a new
1. One of the three anthrax toxins, PA (the bowling-pin
shaped ‘PA83’ in the illustration), binds to a CMG2 receptor on the
surface of a human cell. 2. The two other anthrax toxins, LF and EF (oval
shapes), stick to PA. The toxins and the receptor are wrapped inside a
membrane ball and pulled into the cell. 3. PA transforms its shape and
forms a channel through the membrane ball that allows EF and LF to get
into the main compartment of the cell and cut off distress calls to the
immune system. (Graphic courtesy of Robert Liddington)
Researchers from The Burnham Institute and the National
Institute of Allergy and Infectious Diseases used the SSRL data to
discover the structure of an anthrax toxin bound with a cell receptor.
Bacillus anthracis, the bacteria that causes anthrax
disease, circulates in the bloodstream and produces three toxins. The
toxins enter nearby cells and turn off their distress calls to the immune
system, like an intruder disabling 911 phone access. Without an immune
response, the bacteria keep reproducing and making more toxins.
Eventually, the toxins kill the cells.
To get into cells, one of the toxins—protective antigen
(PA)—binds to a receptor called CMG2 on the surface of human cells. This
triggers the joined pair—to which the two other anthrax toxins are
attached—to be wrapped inside a membrane ball and moved inside the cell.
PA takes advantage of the receptor and a natural change in the ball’s
acidity to change its shape.
"PA makes a big loop, a long hairpin structure that pokes
through the membrane of the ball," said Robert Liddington (Burnham
Institute), an author on the recent Nature paper describing this work.
Piercing through the ball membrane allows the toxin to
form a channel, like a straw in a soda. The other two toxins usurp energy
from the cell and use the PA channel to flow out of the ball and into the
main part of the cell where they prevent an immune response.
"The toxin is using natural cellular machinery in a very
creative way," Liddington said. The new information on how PA recognizes
and tricks our cell receptors is potent information for designing
anti-anthrax drugs that derail the PA-CMG2 interaction.
PA also binds to a receptor called TEM8 found primarily on
the surface of cells lining the blood vessels that supply nutrients to
tumors. This scenario for treating cancer involves PA binding to TEM8,
allowing one of the toxins, called lethal factor, to enter and kill
rapidly proliferating cancer cells. PA toxin injected into blood vessels
has already killed tumors in mice. The PA can also enter normal cells via
the CMG2 receptor, but the damage is limited because there are no anthrax
bacteria pumping out huge doses of toxin. To more precisely target cancer,
researchers are looking for differences between TEM8 and CMG2.
"The two receptors are quite similar but probably there
are enough differences to engineer anthrax PA molecules to favor binding
to the TEM8 receptor," Liddington said.