New Analytical Tool to Unravel the Cause of Diabetes

Researchers at the University of Wisconsin-Madison have designed a powerful analytical tool capable of measuring molecular structures quickly and accurately enough to catch moving proteins in mid-fold and see the shapes of intermediate steps.

And what has the chemists really excited, is that the first applications of the technique offer a glimpse into the contorted form of a human protein that is implicated in type II diabetes.

Pancreatic damage in type II diabetes has been linked to toxic clumps of the protein hIAPP (human islet amyloid polypeptide), which is normally produced by the same cells that make insulin.

An unknown trigger prompts the protein to fold into sharp fibers that poke holes in pancreatic cells, killing them.

Though scientists already have a good idea of the healthy "before" and dangerous "after" hIAPP structures, the steps in between remain somewhat of a mystery and may hold clues to what drives the transition.

Researchers led by UW-Madison chemistry professor Martin Zanni, used a method, known as two-dimensional infrared spectroscopy (2-D IR for short), that takes advantage of the restless nature of molecules and atoms to break down this dynamic process.

They obtained a single structural scan of hIAPP in less than a second - more than 500 times faster than previously possible.

This speed is crucial for trying to understand a dynamic process like hIAPP mis-folding, Zanni says.

The group now plans to capture series of snapshots during individual folding reactions to identify multiple phases as the proteins convert from an unordered mishmash into flat sheets, then coil into fibers.

"No matter how fast they're moving, we can take pictures of them. We need tools that not only allow us to probe the molecular structures, but also look at how the structures change in time," says Zanni.

Though often depicted as static blobs, proteins are more like collections of balls and springs, constantly in motion, and their endless atomic twitching conveys information about their organization. Infrared laser beams can detect the minute vibrations and identify characteristic patterns to deduce protein structures.

The technique also has potential application in other human diseases that involve protein mis-folding, such as Alzheimer's and Huntington's diseases.

The study appears in the online issue of the Proceedings of the National Academy of Sciences.

Source-ANI
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