New structural studies show that the filaments that make up amyloid deposits look like nearly closed stuck zippers. Once amyloid fibrils form in tissues and cells, they resemble a towering stack of zippers, each tightly bonded to the one below.

A chance meeting with an old friend helped solve a problem that had stymied David Eisenberg's research team for years—and led to a breakthrough discovery. In 2000, the HHMI investigator's group at the University of California, Los Angeles (UCLA), identified a short peptide chain from the yeast protein Sup35, which, like a full-length protein, could form amyloid fibrils—thread-like abnormal protein deposits involved in a host of deadly disorders, including Alzheimer's disease, Parkinson's disease, type II diabetes, and the human counterpart of mad cow disease.

The next logical step, says Eisenberg, was to determine the peptide's atomic structure. This is a prerequisite to devising drugs that might prevent these lethal molecules from forming in the first place, says Jiri Safar, a scientist at the Institute for Neurodegenerative Diseases at the University of California, San Francisco (UCSF), "and developing diagnostic tools to detect their presence long before symptoms appear, to prevent irreparable damage."

To decipher the three-dimensional structure of this biologically important molecule, Eisenberg coaxed the proteins into forming crystals. That way, he could use a technique known as x-ray crystallography, which relies on the ability to get proteins into a crystal form. But the task proved daunting because the microcrystals formed by the peptide, which is composed of just seven amino acids, were impractically tiny—some 50,000 times smaller than the crystals researchers normally work with.

Image: David Eisenberg, HHMI at UCLA. Image reprinted courtesy of Nature, vol. 435, pp. 773 to 778.

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