The saliva from a poisonous reptile is helping in the understanding of the causes of Alzheimer's and Parkinson's diseases, writes Dick Ahlstrom
Gila monster saliva is helping to advance our understanding of human conditions such as Alzheimer's disease. This poisonous lizard lives in the deserts of the southwest US, but its saliva contains one of the smallest proteins yet discovered, one that is proving quite valuable.
This same "miniprotein" happens to hold the record for the fastest folding protein known. Once formed into a fresh string of just 20 amino acids, it folds down into its proper shape in just four millionths of a second. Understanding how proteins fold and, importantly, why they sometimes misfold is a hugely important research area, according to Dr Ken Hun Mok, a biochemistry lecturer at Trinity College Dublin.
... "Many of the degenerative diseases such as Parkinson's and Alzheimer's diseases, BSE in cattle and its human equivalent vCJD are all similar in that they are typified by protein gunk, the proteins are not getting folded into their proper structure and so are unable to function as nature intended," he explains. Folding is essential when it comes to proteins. DNA provides the initial amino acid "recipe" for the protein and, once made into a string of amino acids in the cell, it contracts and twists into a shape unique to each protein. Its shape, in turn, dictates its function. The protein must have the correct shape to work properly and many diseases are caused when a protein hasn't folded properly.
Dr Mok's work is all about understanding protein folding. He published a paper on the subject earlier this month in the journal Nature, which described a new method for studying the folding process.
His protein of choice was the "Trp-cage" protein from the Gila monster, both because of its compact size and because it has been studied extensively. "The protein we are looking at is very interesting. It is the smallest known protein because it contains all the features seen in a full protein but is just 20 amino acids long," Dr Mok explains.
"I look at the atomic details of protein molecules and the folding of proteins," he says. "If there is a way to inhibit the improper folding of a protein we may be able to prevent disease. If we understand why they fold perhaps we can understand why they misfold."
The problem is that proteins are extremely complex molecules and the folding process happens very quickly. Folding is driven by the natural attraction and repulsion between atoms in a molecule, akin to the way a box full of small magnets will clump together or push away, depending on the force fields around them. "We know what the forces are but the forces are very finely balanced. If one of them goes a little haywire you will not get proper folding," says Dr Mok. "I use nuclear magnetic resonance (NMR) spectroscopy to study protein folding." He has developed a new more powerful method which combines spectroscopy with laser light to trigger protein refolding.
A properly folded protein springs down into a tight structure, but an improperly folded molecule has "floppy regions" that have not packed down, says Dr Mok. He uses the NMR system to look specifically at these floppy regions, targeting them with laser light.The light tags the floppy region in a process known as "pulse labelling" and when read afterwards by the NMR system it provides more information about the unfolded region. "We have developed a new method of using NMR spectroscopy. The spectra change if the protein is partially folded or misfolded," he says.
He began the work in the University of Oxford's department of chemistry, working with Prof Peter J Hore who is a listed author on the paper, with others. Dr Mok completed the research work at Trinity before submitting for publication as first author.
"It is a small step," he says modestly. The next is to apply the new technique to the more complex proteins directly associated with Alzheimer's disease which cause the buildup of amyloid plaques in brain tissue. ... ...