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Loren Walensky, MD, PhD
Scientists at Dana-Farber Cancer Institute have identified a
previously undetected trigger point on a naturally occurring "death
protein" that helps the body get rid of unwanted or diseased cells. They
say it may be possible to exploit the newly found trigger as a target
for designer drugs that would treat cancer by forcing malignant cells to
Loren Walensky, MD, PhD, pediatric oncologist and chemical biologist
at Dana-Farber and Children's Hospital Boston, and colleagues report in
the Oct. 23 issue of the journal Nature that they directly
activated this trigger on the "executioner" protein BAX, killing
laboratory cells by setting in motion their self-destruct mechanism.
The researchers fashioned a peptide (a protein subunit) that
precisely matched the shape of the newly found trigger site on the
killer protein, which lies dormant in the cell's interior until
activated by cellular stress.
When the peptide docked into the binding site, BAX was spurred into
assassin mode. The activated BAX proteins flocked to the cell's power
plants, the mitochondria, where they poked holes in the mitochondria's
membranes, killing the cells. This process is called apoptosis, or
programmed cell death.
"We identified a switch that turns BAX on, and we believe this
discovery can be used to develop drugs that turn on or turn off cell
death in human disease by targeting BAX," said Walensky, who is also an
assistant professor of pediatrics at Harvard Medical School.
BAX is one of about two dozen proteins known collectively as the
BCL-2 family. The proteins interact in various combinations leading to
either the survival of a cell or its programmed self-destruction. Cancer
cells have an imbalance of BCL-2 family signals that drives them to
survive instead of dying on command.
The late Stanley Korsmeyer, MD, an apoptosis research pioneer and
Walensky's Dana-Farber mentor, had suggested that killer proteins like
BAX could be activated directly by "death domains," termed BH3,
contained within a subset of BCL-2 family proteins. He hypothesized that
this activating interaction was a fleeting "hit-and-run" event, making
it especially challenging for scientists to study the phenomenon.
As suspected, the proposed BAX-activating interactions could not be
captured by traditional methods. "When you tried to measure binding of
the BH3 subunits to BAX, you couldn't detect the interaction," explained
Walensky. He recognized, however, that the BH3 peptides being used in
the laboratory didn't retain the coiled shape of the natural BH3 domains
that participate in BCL-2 family protein interactions.
Walensky and his colleagues pioneered the design of "stapled" BH3
peptides, which contain a chemical crosslink that locks the peptides
into their natural coiled shape. With biologically active shape
restored, the stapled BH3 peptides bound directly to BAX and triggered
its killer activity.
Defining how the activating peptides docked on BAX remained a
formidable catch-22. In order to solve the structure of an interaction
complex, it needed to be stable enough for analysis. In this case, the
BH3 binding event itself triggers BAX to change its shape and
self-associate to perform its killer function, rendering the activating
interaction unstable by definition.
What if, Walensky proposed, you could set up the interaction of BH3
and BAX under laboratory conditions that caused it to be more stable or
proceed in slow motion?
The plan was to adjust the potency of the stapled BH3 peptide so
that, according to Walensky, "it was good enough to bind BAX, yet
activate it just a bit more slowly so that we could actually study the
interaction." The researchers would then look for any detectable shift
in the three-dimensional structure of the BAX protein to help point them
to the docking site.
The researchers used nuclear magnetic resonance (NMR) spectroscopy to
monitor the arrangement of atoms in the protein. First authors of the Nature
paper Evripidis Gavathiotis, PhD, of Walensky's laboratory and Motoshi
Suzuki, PhD, of Nico Tjandra, PhD,'s laboratory at the National
Institutes of Health, succeeded in generating pure BAX protein that
could be put into solution with the stapled BH3 peptide — the latter in
increasing concentrations until it initiated a BH3-BAX interaction.
Gavathiotis and Suzuki used the NMR technique to spot a group of BAX
amino acids, the building blocks of proteins, which were affected by the
addition of the stapled BH3 peptide.
"The discrete subset of amino acids that shifted upon exposure to the
stapled BH3 peptide mapped to a completely unanticipated location on
BAX," said Walensky. The long-elusive binding site on BAX that initiates
its killer activity was revealed.
"Because BAX lies at the crossroads of the cell's decision to live or
die, drugs that directly activate BAX could kill diseased cells like in
cancer and BAX-blocking drugs could potentially prevent unwanted cell
death, such as in heart attack, stroke, and neurodegeneration," said
Additional authors include Marguerite Davis, Kenneth Pitter, Gregory
Bird, PhD, and Samuel Katz, MD, PhD, of Dana-Farber, and Ho-Chou Tu,
Hyungjin Kim, and Emily H.-Y. Cheng, MD, PhD, of Washington University
School of Medicine. The research was supported, in part, by a grant from
the National Institutes of Health.
Dana-Farber Cancer Institute (www.dana-farber.org)
is a principal teaching affiliate of the Harvard Medical School and is
among the leading cancer research and care centers in the United States.
It is a founding member of the Dana-Farber/Harvard Cancer Center
(DF/HCC), designated a comprehensive cancer center by the National