Protein structure may lead to treatment for infection targeting
cystic fibrosis patients
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ARGONNE, Ill. (June 9, 2006) – Researchers at the U.S. Department
of Energy's Argonne National Laboratory have determined the structure
of a key protein believed to play a role in a deadly infection
that afflicts the lungs of cystic fibrosis patients. This finding,
published in today's issue of Science,
may lead to a new drug to treat the bacterial infection.
Pseudomonas aeruginosa, a pathogen that infects more than 80 percent
of cystic fibrosis patients, is a leading cause of these patients' deaths. P.
aeruginosa is difficult to treat because it is resistant to many drugs.
While working through a number of pathogenic proteins, Argonne protein crystallographer
Marianne Cuff's keen eye caught a glimpse of a bagel-shaped pore. Closer inspection
revealed a six-sided ring that she believed "might be involved in transferring
toxins into cells," she said.
"I thought it would be an important structure," she said. "The
ring is very stable and unusual, and nature usually has a purpose for these
stable forms."
Cuff, who is a co-author of the Science paper, deposited the structure
of the protein, called Hcp1, into the Protein
Data Bank, a resource used by
biologists worldwide to find information about the proteins they are studying.
While exploring the Protein Data Bank, Harvard
Medical School researchers,
who were also studying P. aeruginosa in the laboratory of John Mekalanos,
recognized that the amino acid sequence of Hcp1 in P. aeruginosa closely
resembled that of Hcp1 in Vibrio cholerae. The Mekalanos lab had previously
discovered that the Hcp1 protein of V. cholerae is released
from the bacterium via a novel secretion pathway.
Because Hcp1 proteins from both pathogens belong to the same protein family, Science paper
lead-author Joseph D. Mougous, wondered whether the P. aeruginosa Hcp1
might also be secreted via this pathway. Researchers at Harvard and Argonne
quickly formed a collaboration and confirmed the hypothesis. They then turned
their attention to Hcp1 in cystic fibrosis patients to gain more insight into
the role of Hcp1 during infection.
“Pathogenic bacteria such as P. aeruginosa use protein secretion
systems to cause disease in their hosts,” said Mougous, a research fellow in
the Harvard Medical School Department
of Microbiology and Molecular Genetics. “In
the case of P. aeruginosa, the host may be a cancer patient
with a weakened immune system, a burn patient or a person with cystic fibrosis.
“Cystic fibrosis patients are particularly susceptible to P. aeruginosa,” Mougous
said. “The bacterium thrives in the excess mucus that accumulates in their
lungs. Once the infection in a cystic fibrosis patient's lung has been established,
these hardy bacteria are difficult or impossible to clear, which over many
years eventually results in death of the patient.”
Working with cystic fibrosis patients at Children's
Hospital Boston, the Harvard
Medical School researchers sought and found Hcp1 in the sputum of patients
with P. aeruginosa. They also found Hcp1 antibodies in the patients'
blood – further proof that Hcp1 plays a critical role in the infection. The
human immune system creates antibodies to pathogens it is exposed to.
"This finding provides a possible drug target to fight the infection
in cystic fibrosis patients," explained Andzrej Joachimiak, director of
Argonne's Structural Biology Center and of the Midwest
Center for Structural Genomics based at Argonne, where the protein structure research was performed.
Determining and imaging the structure of the protein Hcp1 was part of the
routine structural biology research Argonne biologists are performing on pathogens
with funding from the National
Institute of General Medical Sciences' (NIGMS)
Protein Structure Initiative. This initiative funds researchers to determine
a number of unique protein structures to serve as a base of knowledge from
which other structures and functions can be inferred.
"This research is an example of how the Protein Structure Initiative
was designed to work," explained Joachimiak. "A structure we determined
led researchers to design an experiment to provide key information about how
a pathogen works. New treatments could be developed from this starting point."
The protein crystallography research was performed at Argonne by researchers
in the Argonne-led Midwest Center for Structural Genomics, funded by NIGMS.
Following the protein cloning, expression, purification and crystallization,
the protein crystallography data were collected at Argonne's Structural Biology
Center at this hemisphere's most brilliant source of X-rays for research – the
Advanced Photon Source. Cuff converted the data into three-dimensional models
that revealed the six-sided pore with the 40-Angstrom wide center.
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The nation's first national laboratory, Argonne conducts leading-edge basic
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the U.S.
Department of Energy's Office
of Science.
Harvard Medical School has more than 7,000 full-time faculty working in eight
academic departments based at the School's Boston quadrangle or in one of 47
academic departments at 18 Harvard teaching hospitals and research institutes.
Those Harvard hospitals and research institutions include Beth Israel Deaconess
Medical Center, Brigham and Women's Hospital, Cambridge Health Alliance, the
CBR Institute for Biomedical Research, Children's Hospital Boston, Dana-Farber
Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Joslin Diabetes
Center, Judge Baker Children's Center, Massachusetts Eye and Ear Infirmary,
Massachusetts General Hospital, Massachusetts Mental Health Center, McLean
Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding
Rehabilitation Hospital, and VA Boston Healthcare System.
For more information, please contact Catherine Foster (630/252-5580 or
cfoster@anl.gov) at Argonne.
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