Engineers Force Open Novel Protein Targets Within Stem Cells And
Blood Cells
Aug. 8, 2007
Science Daily — Applying physical stress to cells, researchers at the
University of Pennsylvania have demonstrated that everyday forces can
alter the structure of proteins tucked within cells, unfold them and
expose new targets in the fight against disease.
The findings for both simple red blood cells and more versatile stem
cells show that hidden and folded parts of proteins can be exposed by
physical strain, not just by chemical reaction. From there, proteins
can be labeled and mapped, increasing the understanding of cellular
behavior and unlocking novel targetable sites for drugs that might
interact with these active proteins to treat disease.
Cells are exposed to forces every minute of every day. Some forces
are exerted by the flow of bodily fluids, such as blood streaming
through arteries, while other forces are generated by cells as they
crawl and contract in tissue.
Penn researchers used force to induce changes in the structures of
cytoskeletal proteins and, employing fluorescent dyes, labeled
proteins sequentially, visualized them, and molecularly pinpointed
the newly exposed parts of proteins. By forcing proteins to unfold,
hidden binding sites were thus revealed. Multicolor maps were
generated that revealed locations of protein sites not accessible
when the cell remained static and relaxed.
"We were motivated to probe molecular mechanics within cells in part
by our recent findings on stem cells that show they generate their
own forces, switching on and off development of different cell
types," Dennis Discher, professor of chemical and biomolecular
engineering at Penn, said.
Proteins are the molecular instigators for almost every biologic
action and reaction in living things. Their assembly and reactions
are the foundation of processes from the division of cells to the
complex chain of events that result in the apparently simple blink of
an eye. Pathophysiological processes such as heart disease, anemia,
and even the rigidification of breast tumors often reflect changes in
protein organization and assembly that adversely affect static and
dynamic forces in, on, and around cells. Protein targeting is the
strategy commonly employed to create new drugs to deal with those
adverse affects.
Cytoskeletal proteins, well-known amongst cell biology and biophysics
researchers, are a leading cause of a large number of diseases
that "mess up" proteins, sometimes misfold them, and often disrupt
their natural interactions as well as those of cells. If stem cells
are to provide hope for therapy, they will certainly rely on the
proper assembly of many cytoskeletal proteins that achieve the right
levels of flexibility and force-generation. Cytoskeletal pliability
within cells under stress has been a matter of guesswork in the past,
however, and so a better understanding, achievable with the molecular
mapping strategy, opens up new approaches for targeting specific
cellular interactions.
Future efforts will focus in part on folding of cytoskeletal proteins
that are targets of gene therapies and also on clarifying signaling
processes in cells that couple to protein folding. The latter
processes often entail modification of proteins with phosphates and
are essential to how individual cells feel the forces exerted on
them. Through a better understanding of how forces localize and
unfold proteins to propagate cascades of protein phosphorylation and
cell activation, new therapeutic strategies are bound to emerge.
The study was conducted by Discher, Colin Johnson, and Christine
Carag of Penn's School of Engineering and Applied Science, as well as
Hsin-Yao Tang and David Speicher of The Wistar Institute at the
University of Pennsylvania. The research was supported by the
National Institutes of Health, the National Science Foundation and
the Muscular Dystrophy Association.
The study appears in the journal Science.
Note: This story has been adapted from a news release issued by
University of Pennsylvania.
http://www.scienced
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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