Decoding protein structures helps illuminate cause of diabetes

May 16, 2007

Any photographer can vouch for the difficulty of capturing a clear picture of a moving target. When it comes to molecules, however, sometimes the motion is exactly what scientists want to see - for example, to understand the pathological protein mis-folding and assembly that seem to underlie a host of human disorders, including diabetes and Alzheimer's disease.

Now, chemists 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. As described in this week's online issue of the Proceedings of the National Academy of Sciences, 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, says UW-Madison chemistry professor Martin Zanni, who led the new study.

In trying to understand diabetes, "people have been looking at the fibers, but they should be looking at their formation," he says. "Somehow that mechanism is causing holes [in pancreas cells], which cause disease."

To break down this dynamic process, he adds, "We need tools that not only allow us to probe the molecular structures, but also look at how the structures change in time."
Zanni's research group uses a method, known as two-dimensional infrared spectroscopy (2-D IR for short), that takes advantage of the restless nature of molecules and atoms.

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, Zanni says. Infrared laser beams can detect the minute vibrations and identify characteristic patterns to deduce protein structures.

A few years ago, Zanni's team built the first device capable of designing infrared laser beams with a computer. The team has now simplified and speeded up the process with an automated version of the 2-D IR technique. As described in the current study, they obtained a single structural scan of hIAPP in less than a second - more than 500 times faster than previously possible.

The 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," says Zanni. Without their automated method, he says, such experiments would be nearly impossible.

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

At this time, however, he says the automation of the device itself is a tremendous achievement. "In time, automated 2-D IR spectroscopy will become a common analytical technique, widely available in university and industrial research laboratories around the world."

Source: University of Wisconsin-Madison

Explore further: Celebrating 100 years of crystallography

add to favorites email to friend print save as pdf

Related Stories

Dolphins and whales experience pleasure

9 hours ago

Sam Ridgway has spent most of his life learning about dolphins and whales. Over his five-decade career he has asked these cetaceans various questions, including how deep they can dive and how depth affects ...

Minke whales lunge 100 times per hour to feed under sea ice

9 hours ago

Highly manoeuvrable and built like torpedoes, minke whales are the most common whales in Antarctic waters, yet the animals could be living on a knife edge as their sea-ice homes dwindle rapidly. 'Sea ice in the area around ...

Cisco to cut 6,000 jobs in streamlining

10 hours ago

US computer networking giant Cisco Systems said Wednesday it plans to slash some 6,000 jobs, or eight percent of its global workforce in the coming year.

Report: NSA eyed preset strikes in cyberattacks

10 hours ago

The National Security Agency secretly planned a cyberwarfare program that could automatically fire back at cyberattacks from foreign countries without any human involvement, creating the risk of accidentally ...

Recommended for you

Celebrating 100 years of crystallography

43 minutes ago

To commemorate the 100th anniversary of a revolutionary technique that underpins much of modern science, Chemical & Engineering News (C&EN) magazine last week released a special edition on X-ray crystallography—its past, ...

Treating pain by blocking the 'chili-pepper receptor'

1 hour ago

Biting into a chili pepper causes a burning spiciness that is irresistible to some, but intolerable to others. Scientists exploring the chili pepper's effect are using their findings to develop a new drug ...

Testing the shelf-life of nuclear reactors

1 hour ago

Researchers at the University of Michigan, Ann Arbor, Los Alamos National Laboratory, Idaho National Laboratory, Idaho Falls and TerraPower based in Bellevue, Washington, have demonstrated the power of high-energy beams of ...

Electronic 'noses' to detect chemical warfare gases

3 hours ago

Researchers of the Universitat Politècnica de València have developed a prototype of electronic "nose" for the detection of chemical warfare gases, fundamentally nerve gases (Sarin, Soman and Tabun). 

User comments : 0