Anthrax, long feared for its potential as a biological weapon, has lost some
of its mystery. Researchers at the U.S.
Department of Energy's (DOE) Argonne National Laboratory, in collaboration
with scientists at the University of Chicago, have determined the structure
of a protein crucial to the virulence of anthrax bacteria.
One of anthrax’s most dangerous features is its ability to exist as a
spore—an inactive sealed package that can survive extreme conditions outside
its host for long periods. Once in the bloodstream, however, the bacterium germinates,
triggering a dangerous infection. The activated anthrax bacterium looks like
a thin rod swathed in a thick protective capsule coating. This capsule coat
lets the bacteria evade macrophages, the roving white blood cells that form
the first line of our immune response.
The researchers examined a gene that codes for a particular enzyme called CapD,
a protein that helps the bacteria form its protective coating once it enters
the body. CapD sits on the surface of the cell, grabs molecules of the capsule’s
building blocks (poly-D-gamma-glutamic acid, or PDGA) and attaches them to the
bacteria’s outer wall to form its shield.
“The PDGA peptide construction is unusual; for example, it is made with
the ‘D’ isomer of glutamic acid instead of the ‘L’ form
found in proteins,” said Andrzej Joachimiak, a co-author of the study.
“This is why macrophages can’t deal with the protective capsule
of anthrax. They could easily find a regular peptide made of ‘L’
amino acids, but this is a unique configuration, and they can’t recognize
it. That’s how they fool the system.”
Joachimiak and the team wanted to map out the crystal structure of CapD. Once
the researchers discovered the enzyme's structure, they could begin to search
for a molecule that could block its function—which in turn would make
the bacteria more vulnerable to human defenses.
By using brilliant X-rays at the Structural Biology Center 19ID beamline at
Argonne's Advanced Photon Source, the team was able to image two versions of
the protein: one with a molecule of imitation capsule material attached, and
“It looks like Pac-Man,” Joachimiak said. “The jaws are open
when it’s empty, but when the ligand attaches, it clamps down around it.”
Then the enzyme cleaves the polymer and attaches it to the surface of the cell.
The paper, “Crystal Structure of Bacillus anthracis Transpeptidase Enzyme
CapD”, will be published in the Journal of Biological Chemistry.
The work to characterize anthrax and other pathogenic or important bacteria
is part of an initiative by the Midwest Center for Structural Genomics, an NIH-funded
consortium of eight institutions, and the Region V Great Lakes Regional Center
of Excellence in Biodefense and Emerging Infectious Diseases Consortium.
Funding for this research was provided by the National Institutes of Health
(NIH), the National Institute of General Medical Sciences (NIGMS), and the National
Institute of Allergy and Infectious Disease (NIAID) Regional Centers of Excellence.
The Advanced Photon Source is supported by the Office of Basic Energy Sciences
within the DOE Office of Science.
Argonne National Laboratory seeks solutions to pressing national problems in
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leading-edge basic and applied scientific research in virtually every scientific
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of Energy's Office of Science.