The breakthrough came when the researchers teamed up with European crystallographer Christian Riekel, who had designed and built a special x-ray beam as narrow as the crystals were tiny, and Anders Madsen, a Danish student working at the synchrotron in France who was skilled in special methods for mounting and manipulating the samples to collect good x-ray diffraction data.
"With the first calculation, we were able to see the structure and how we would be able to model atoms into that map," Nelson said. "That was really the ah-ha moment."
The final detailed structure is broadly consistent with other lower-resolution models, such as the two stacked beta sheets composed of the main chain of amino acids. The surprise came with the molecular side chains that give each amino acid its unique identity and hold the pairs of beta sheets in formation.
Nelson expected to see only the ends of the side chains reaching out and touching each other, they way they do in the DNA double helix. Instead, she found interdigitated connections akin to zippers and Velcro.
"This gives a structural explanation about why the fibers grow almost infinitely, and why prions are infectious," said Roland Riek of The Salk Institute. "Like a zipper, you have one end that never ends; you always have a free binding site for a growing fiber." In a related paper in Nature, Riek reported that the infectious ability of a fungal prion depends on its beta sheet structure, which he proposed would look similar to the detailed structure from Eisenberg's lab.
In another interesting finding, the zipped up fibril core is dry. "Proteins love water," said Eisenberg. "When they are soluble, there is water all around them. When the z
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
8-Jun-2005