NC State Scientists Characterize Protein Linked To Neurodegenerative Diseases

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NC State Scientists Characterize Protein Linked To Neurodegenerative

Diseases

http://www.medicalnewstoday.com/medicalnews.php?newsid=48088

Dr. 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. "

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The National Institutes of Health, the American Foundation for Aging

Research and the Kenan Institute for Engineering, Technology &

Science supported the research.