Zanni and collaborators showed that the floppy FGAIL region can contribute to the formation of plaque, but first, the amylin proteins must clump together in an arrangement in which the FGAIL region is indeed a rigid beta-sheet.
"That 30-year-old hypothesis is partly correct: the FGAIL region does indeed form the beta-sheets, but only for a little while until those sheets are broken to make the flexible loop," Zanni says.
The intermediate clumping step is where animal species resistant to type 2 diabetes are making their move.
"Our results indicate that the proteins in rats, dogs and other animals do not stop the plaques themselves, but instead target this upstream step," Zanni says, "preventing the intermediate from forming and thereby the plaques as well."
Using a technique called two-dimensional infrared spectroscopy developed in Zanni's lab, the new study which included collaborators at the University of California, Irvine, University of Chicago, Argonne National Lab and State University of New York at Stony Brook provides the first picture containing specific details of what the intermediate clumps look like.
"Good drugs work by fitting into nooks and crannies," says Zanni, whose work is funded by the National Institutes of Health. "Thus, it is much easier to design a drug when the shape of the toxic protein is known, which is what our data is beginning to provide."
|Contact: Martin Zanni|
University of Wisconsin-Madison