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♦ See referenced article, J. Biol. Chem. 2012, 287, 5235–5241
Type 2 diabetic patients carry misfolded proteins in the form of fibrils in their pancreases. These fibrils are composed mostly of human islet amyloid polypeptide, a protein co-secreted with insulin, and are thought to be critical for disease progression, but the details of their structure are unknown. In this Paper of the Week, Ralf Langen at the University of Southern California and colleagues analyzed the fibrillar structure at the atomic level. They combined site-directed spin labeling with continuous wave and pulsed electron paramagnetic resonance, which gave information about both the short- and long-range distances between atoms. The investigators found that each protein molecule formed a hairpin with two β-strands. The hairpin molecules stacked on top of each other in a staggered formation to create a left-handed helix. The model can help researchers understand the formation and stability of the fibrils, as well as provide ways to develop therapeutics against this disease and other disorders, such as Alzheimer disease, that involve protein misfolding.