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A ‘shock’ to the system
November 2015
by Mel J. Yeates  |  Email the author
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MUNICH, Germany—Small heat shock proteins are the “catastrophic aid workers” of the cell. In Alzheimer’s disease, beta amyloids agglomerate to form long fibrils in the nerve cells. Once these clumps have formed, the proteins become useless and the nerve cells begin to die. But if small heat shock proteins attach to the deformed proteins before they clump together, and preserve them in a soluble state, they help to restore the deformed proteins’ proper form.
 
Scientists, therefore, hope to deploy small heat shock proteins as agents in the treatment of neurodegenerative diseases. A group of researchers led by Bernd Reif, a professor in the Department of Chemistry of the Technical University of Munich (TUM) and group leader at the Helmholtz Zentrum München, has now succeeded in uncovering the mechanism by which alpha-B-crystallin (a heat shock protein) attaches to its disease-causing counterparts, such as beta-amyloid.
 
Using a refined procedure of solid-state nuclear magnetic resonance spectroscopy (solid-state NMR), the researchers managed, for the first time ever, to identify the sites in the alpha-B-crystallin that attach to the beta-amyloid. As Reif tells DDNews, NMR spectra are sensitive to the chemical environment. If a ligand such as beta-amyloid binds to the surface of alpha-B-crystallin, the researchers observe defined chemical shift changes that are indicative for ligand binding.
 
It is the first direct structure analysis of a complete heat shock protein during interaction with a bonding partner, because the small heat shock proteins do not make the observers’ job easy. “Alpha-B-crystallin exists in various different forms comprising 24, 28 or 32 subunits that are permanently being swapped,” explained Reif. “In addition, it has a large molecular weight. These factors make structure analysis very difficult.”
 
In close collaboration with his TUM colleagues Johannes Buchner, a professor of biotechnology, and Sevil Weinkauf, a professor of electron microscopy, Reif determined that alpha-B-crystallin uses a specific non-polar beta-sheet structure pile in its center for interactions with the beta-amyloid, allowing it to access the aggregation process in two locations at once. It attaches to individual dissolved beta-amyloids, preventing them from forming fibrils. In addition, it “seals” existing fibrils, so that further amyloids can no longer accumulate.
 
Precise knowledge about the way in which alpha-B-crystallin attaches to the Alzheimer’s protein is particularly interesting for researchers using so-called “protein engineering” to develop new agents that bind specifically to beta-amyloid and similar proteins. If the newly discovered beta-sheet structure idea can be integrated as building blocks into such artificially designed proteins, it will improve the proteins’ ability to attach to the disease-causing fibrils—a first step in the development of new agents against Alzheimer’s and other neurodegenerative diseases, such as Parkinson’s disease and multiple sclerosis.
 
“It’s important to know which residues and secondary structure elements in alpha-B-crystallin are involved in the interaction with beta-amyloid, for protein engineering,” says Reif. “This knowledge might allow researchers to design affibodies with increased binding affinities.”
 
In future work, the scientists want to take a closer look at the N-terminal region of the alpha-B-crystallin. As Reif and his colleagues have discovered, it binds protein types that, unlike the beta-amyloid, clump together in an unordered manner.
 
“At the moment we are pursuing phosphorylated alpha-B-crystallin, which is known to have an increased chaperone activity,” Reif explains. “We would like to know what effect this phosphorylation has on the assembly of the alpha-B-crystallin oligomer. So far, we do not plan to work with artifical protein constructs, but we will follow the literature on this topic closely.”
 
The researchers will be supported by the new NMR Center that is currently under construction at the Garching campus of the Technical University of Munich, slated to open in 2017. A further €5-million facility geared specifically to solid-state NMR is currently under construction at the Helmholtz Zentrum in Neuherberg.
 
This research was funded by the Helmholtz Zentrum München and the German Research Foundation. The research of this publication started at the Leibniz-Institut für Molekulare Pharmakologie in Berlin.
 
Code: E111504

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