MUNICH, Germany---Small heat shock proteins are a type of protein that are constantly present, but are highly expressed when cells are exposed to stressful conditions and function as “catastrophe aid workers.” Cell proteins lose their structure and form tangled clumps when exposed to strong heat or radiation, after which they become useless and begin to die. Small heat shock proteins attach to these deformed proteins before they clump together and help to maintain their soluble state, which helps restore them to their proper form.
Heat shock proteins are present in all types of cells, capable of binding large numbers of misfolded proteins, and are associated with nervous system disorders such as Parkinson's disease and multiple sclerosis. The disease in which their natural function is particularly promising, however, is Alzheimer's disease, which is characterized by the beta amyloid plaques that develop in the brains of patients, tangles of proteins that clump together to form fibrils in the nerve cells.
Up until now, it hasn't been known exactly what role heat shock proteins play in various diseases, but a team of researchers led by Bernd Reif, professor at the Department of Chemistry of the Technical University of Munich (TUM) and group leader at the Helmholtz Zentrum München, recently uncovered the mechanism by which these proteins target and bind with deformed proteins. The team applied a refined procedure of solid-state nuclear magnetic resonance spectroscopy (solid-state NMR), and identified sites in the alpha-B-crystallin that attach to beta amyloid, marking the first direct structure analysis of a complete heat shock protein during interaction with a bonding partner.
“Alpha-B-crystallin exists in various different forms comprising 24, 28 or 32 subunits that are permanently being swapped,” explains Reif. “In addition, it has a large molecular weight. These factors make structure analysis very difficult.”
Reif, along with TUM colleagues Johannes Buchner, professor of biotechnology and Sevil Weinkauf, professor of electron microscopy, found that the heat shock protein makes use of a specific non-polar beta-sheet structure pile in its center for interactions with the beta-amyloid. This allows it to access the aggregation process in two locations simultaneously, by attaching to individual dissolved beta amyloids to prevent them from forming fibrils and by “sealing” existing fibrils so that additional amyloids can't accumulate. The research, which originated at the Leibniz-Institut für Molekulare Pharmakologie in Berlin, was funded by the Helmholtz Zentrum München and the German Research Foundation and the Excellence Cluster “Center for Integrated Protein Science Munich.”
Beyond elucidating how heat shock proteins work, this discovery could also aid researchers investigating protein engineering to develop agents that can specifically bind to beta amyloid and similar proteins. If it's possible to translate the knowledge about the beta-sheet structure into building blocks for engineered proteins, it would offer a new way to target and bind to the fibrils of Alzheimer's disease.
Moving forward, the team next wants to examine the N-terminal region of the alpha-B-crystallin, which binds protein types that clump together in an unordered manner, unlike beta amyloid. The team will be supported by the new NMR Center, which is currently under construction at the Garching campus of TUM and expected to open in 2017. Another 5-million Euro facility tailored for solid-state NMR is currently under construction at the Helmholtz Zentrum in Neuherberg.
SOURCE: Technical University of Munich press release
This person does not yet have a bio.View Full Profile
