Researchers Discover That Small Shape Changes Lead to Increased Protective Ability in a Disease-Related Protein

Top Quote Researchers have found that evolutionary changes in the protein alpha A-crystallin have altered its ability to protect other proteins from damage, which could otherwise result in diseases such as Alzheimer's, lens cataracts and cancer. End Quote
  • Cleveland-Lorain-Elyria, OH (1888PressRelease) March 30, 2012 - Researchers at Ashland University, Miami University (Ohio), and the National Institutes of Health have used a novel approach to show how evolutionary changes in the protein alpha A-crystallin have altered its ability to protect other proteins from damage during periods of physiological stress.

    Alpha A-crystallin is a member of the small heat shock protein family, which plays a role in the prevention of human diseases such as Alzheimer's, lens cataracts and cancer. By comparing alpha A-crystallins from six different fish species, the researchers were able to identify two small changes in the protein's structure that affected its stability and ability to buffer other proteins from stress.

    "The findings provide a unique perspective on the function of these 'stress proteins' and suggest ways that they could be altered to modify their protective abilities," said lead author Dr. Mason Posner, professor of biology at Ashland University.

    The work will be published in PLoS One, a premier open access online journal, on March 29, 2012.

    "We have used a classic comparative biology approach to find how nature alters this small heat shock protein to function in different settings," Posner said. "Most work on these proteins focuses on individual species, and usually mammals. By using fishes as a model group, we have shown how comparing multiple species can identify small changes in protein structure with large effects on function, while still maintaining a viable molecule that does not cause disease."

    Posner said "Not only does this add to our basic understanding of how small heat shock proteins work, but it validates a technique for identifying small heat shock protein modifications that could have therapeutic applications."

    After cloning the gene for one specific small heat shock protein, alpha A-crystallin, from six different fish species living at temperatures from -2 to 40 degrees Celsius, the authors of this study discovered that the protective function and stability of the resulting proteins correlated with the temperature of each fish, Posner said.

    Using computer modeling to compare the structures of each protein and evolutionary analysis to reconstruct the likely changes in those structures during each species' evolution, the researchers identified three amino acid changes that could account for differences in protein function.

    "By genetically engineering zebrafish alpha A-crystallins with amino acid substitutions found in the Antarctic toothfish, the authors were able to show that two of these three changes alter alpha A-crystallin protective function in a predictable way," he said.

    Posner said that "with one small change we were able to produce a zebrafish protein that behaved more like a cold-adapted Antarctic fish protein." While the newly published results were done in vitro, follow up studies will examine the effects of these modified proteins in a live zebrafish, he added.

    Posner said additional future work will examine whether similar modifications can be used to alter human small heat shock proteins.

    Two of the co-authors on this study were undergraduate research students from Ashland University, a medium sized comprehensive Masters university in Ohio with a tradition of strong undergraduate research. The study was funded by the National Eye Institute of the National Institutes of Health.

    Ashland University, ranked in the top 200 colleges and universities in U.S. News and World Report's National Universities category for 2012, is a mid-sized, private university conveniently located a short distance from Akron, Cleveland and Columbus, Ohio. Ashland University values the individual student and offers a unique educational experience that combines the challenge of strong, applied academic programs with a faculty and staff who build nurturing relationships with their students.

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