Structure of calbindin-D28K Protein Involved in Preventing Alzheimers, Huntingtons Diseases Characterised
Jul 26, 2006 - 12:22:00 PM
, Reviewed by: Ankush Vidyarthi
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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, its like hitting all the keys of a piano at the same time and its just an awful mess."
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By NC State University,
[RxPG] 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 Alzheimers and Huntingtons.
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 proteins 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.
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 dont know the shape of the protein, you cant figure out how it works, Cavanagh says. It took a long time about five years but weve 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 Earths 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, its like hitting all the keys of a piano at the same time and its just an awful mess. And remember, were doing this for 5,000 separate keys. Yet, were able to untangle this mess to find the specific frequency of each nucleus and relate that to where it lies in the protein.
Cavanagh isnt 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 were working to determine the structure of this protein when it has no calcium.
Publication:
The research appears in the July 2006 edition of Nature Structural and Molecular Biology.
On the web:
www.ncsu.edu 
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Additional information about the news article
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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.
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