Researchers Detail Snapshot of Proteins That Cause Type 2 Diabetes

Lipid nanodiscs stabilize misfolding protein intermediates red-handed

When proteins misfold, accumulate, and clump in insulin-producing cells in the pancreas, they can kill these cells. Now, researchers at the Technical University of Munich (TUM), the University of Michigan, and the Helmholtz-Zentrum Muenchen have obtained a structural snapshot of these proteins when they are most toxic, detailing them down to an atomic level. The researchers hope this kind of detail can help in the search for drugs to target the incorrectly folding proteins.

The clumps caused by misfolded proteins, called plaques, are implicated in many diseases: plaque interferes with neuron function in the brains of people with dementia and Alzheimer’s. The process of the formation of plaques also kills islet cells, which produce insulin to metabolize sugar, in people with type 2 diabetes.

“In general, toxicity to cells is extremely difficult to prove and characterize,” says Ayyalusamy Ramamoorthy, professor at the University of Michigan and Hans Fischer Fellow of the Institute for Advanced Study at the Technical University of Munich. “On the other hand, we need to do this in order to develop drugs for potential treatment.”

Lipid Nanodiscs Stabilize Aggregating Proteins

To understand the critical protein structures, the researchers used “sushi-like” nanodics composed of layers of lipids surrounded by a belt to capture model proteins during the aggregation process.

The researchers allowed the proteins to fold to a certain point within the nanodisc – when they think the folding proteins are most toxic to islet cells – and then used nuclear magnetic resonance (NMR) spectroscopy to take atomic-level images of the proteins.

“The nanodiscs are like the difference between a swimming pool and the ocean. In the ocean, there are no boundaries; a swimming pool has boundaries,” Ramamoorthy says. “We’re able to stop the aggregation of the protein in this restricted membrane environment so we can monitor what it looks like before it becomes a mass of fibers.”

A First Step into Development of Drugs

The ability to pin down proteins while they’re in the process of amyloid aggregation in a stable manner allow their characterization using a variety of biophysical tools including fluorescence, mass-spectrometry, NMR, and cryo-electron-microscopy. Therewith the researchers hope to both develop and screen for drug compounds that can target the misfolding proteins that are implicated in these diseases.

“We are now screening interactions with small molecule compounds to see if we can inhibit the aggregation process that produces amyloids,” Ramamoorthy says. “This has been much wanted and much awaited information – for the scientific understanding of the pathology of amyloid diseases, and for the development of compounds to overcome these problems.”