USC Research Reveals Clues about Structure of Proteins in Type 2 Diabetes

Dr.Langen HaworthBy Leslie Ridgeway

LOS ANGELES – Research by Keck School of Medicine of the University of Southern California (USC) and USC School of Pharmacy scientists has revealed a new clue about the structure of proteins involved in type 2 diabetes that could eventually lead to the design of a drug to treat neurodegenerative diseases.

Using a new approach to view structures generated in disease called fibrils, the researchers were able to explain the overall rope-like structure of the fibrils formed by proteins in type 2 diabetes, as well as the mechanism by which the structures form. This is important information for researchers working to develop therapies to attack type II diabetes and other neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.

“If we can understand what makes these proteins go bad and what they look like, we can develop drugs to treat type 2 diabetes and other related diseases,” said Ralf Langen, Ph.D., professor of biochemistry and molecular biology in the Keck School and corresponding author on the study. Langen’s research group collected the key data on the fibrils using an EPR technique that takes advantage of “spin labels” placed in key places on the protein. These results were then used to generate the fibril structures using computational methods.

Ian Haworth, Ph.D., associate professor in the USC School of Pharmacy and the lead researcher in the computational work, added “It’s a great example of using basic science methodology to address health-related problems and promote translational research.”

The research, “Fibril Structure of Human Islet Amyloid Polypeptide,”
was published online ahead of print as a Paper of the Week in the Journal of Biological Chemistry.

The fibrils are contained in proteins that change shape, clump together and deposit in affected areas of the body in patients suffering from type 2 diabetes, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.

To get a higher resolution view of the fibrils formed in type 2 diabetes, the researchers developed an approach combining site directed spin labeling with continuous wave and pulsed electron paramagnetic resonance (EPR) as well as computational refinement.

Type 2 diabetes, also known as adult-onset diabetes, is the most common form of diabetes. Patients with this chronic condition do not produce enough insulin, or certain cells do not respond to insulin (also known as “insulin resistance”). The result is high levels of glucose in the blood. The disease can be attributed to family history and genes, but patients also may be overweight.

Lead author of the study is Sahar Bedrood. Contributing researchers include Yiyu Li (USC School of Pharmacy), Jose Mario Isas, Balachandra G. Hegde, Ulrich Baxa (National Institutes of Health) and Ian S. Haworth (USC School of Pharmacy).

This study was funded by the National Institutes of Health.

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Article cited:
Bedrood, S., Li, Y., Isas, J.M., Hegde, B., Baxa, U., Haworth, I.S., Langen, R.
Fibril Structure of Human Islet Amyloid Polypeptide Published online Dec. 20, 2011, Journal of Biological Chemistry, doi: 10.1074/jbc.M111.327817
jbc.M111.327817.

Caption:
School of Pharmacy associate professor Ian Haworth and Keck School of Medicine professor Ralf Langen.