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Scientists
discern shape of important protein linked to Alzheimer’s,
Huntington’s
Newswise — Scientists at North
Carolina State University have effectively lifted the veil from an
important protein that is linked to the prevention of
neurodegenerative diseases like Alzheimer’s and Huntington’s.
Dr. John Cavanagh, professor of
molecular and structural biochemistry, teamed with colleagues from
the Mayo Clinic and Duke University to describe the shape of the
protein, calbindin-D28K. Understanding a protein’s structure allows
researchers to learn more about how it functions and interacts with
other proteins, which, in this case, may provide clues to developing
drugs to halt the diseases.
The research appears in the July
2006 edition of Nature Structural and Molecular Biology.
Calbindin-D28K is a protein that
either grabs calcium from areas that have too much or serves as an
on/off switch for further chemical reactions. It is known for its
flexibility; it is found in the kidneys, pancreas, ocular nerve and
in abundant quantities in the brain. Recent studies show, Cavanagh
says, that it acts as a bodyguard in the brain, binding to and
inhibiting caspase-3, a protein that stimulates plaque formation and
tangle formation, which are hallmark characteristics of
neurodegenerative disease. Until now, however, the structure of
calbindin-D28K remained a mystery.
“If you don’t know the shape of
the protein, you can’t figure out how it works,” Cavanagh says. “It
took a long time – about five years – but we’ve characterized the
structure of this protein and found where it binds caspase-3.
Insight into how it binds to caspase-3 might lead to a way of
exploiting those interactions to develop therapeutics.”
It took a long time to
characterize calbindin-D28K, Cavanagh says, because it was initially
a challenge to force cells to make enough protein in order to do the
requisite studies. Additionally, many parts of the protein are very
similar and so are extremely difficult to distinguish from each
other.
The research team used nuclear
magnetic resonance to get a high-resolution picture of what the
protein looks like. In this painstaking technique – occurring inside
machines that have magnetic fields several hundred times greater
than the Earth’s magnetic pull – radio waves are bounced off the
approximately 5,000 nuclei in the protein.
“When you hit a nucleus with a
radiofrequency pulse, it resonates, sort of making its own little
noise, like a tuning fork,” Cavanagh says. “The frequency at which
the nuclei resonate after being hit with a pulse is very specific to
their specific position in the protein. So after we hit all of them
with a pulse, it’s like hitting all the keys of a piano at the same
time and it’s just an awful mess. And remember, we’re doing this for
5,000 separate keys. Yet, we’re able to untangle this mess to find
the specific frequency of each nucleus and relate that to where it
lies in the protein.”
Cavanagh isn’t satisfied with this
knowledge, however. He says the shape-shifting protein sometimes
contains no calcium. When it grabs calcium, it changes its shape.
“This could be why the protein
plays so many different roles,” Cavanagh says. “Proteins that change
shape usually serve as on/off switches, but this protein also grabs
calcium and takes it elsewhere. Now we’re working to determine the
structure of this protein when it has no calcium.”
The National Institutes of Health,
the American Foundation for Aging Research and the Kenan Institute
for Engineering, Technology & Science supported the research.
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