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Findings upend thinking on shape of pivotal protein

CALL TO ORDER: Scientists have discovered that, within healthy cells, single chains of the alpha-synuclein protein cluster to form four-chain units that twine together in an orderly fashion. Image: Protein Databank ID: 1XQ8, rendered with VMD When it comes to proteins, function follows form. Each twist and turn in the chain of amino acids making up a protein con­trib­utes to its unique properties and behavior, so it's critical for scientists to accurately describe the arrange­ment of folds. But sometimes, they get the entire pattern wrong.

Consider, for example, alpha-synuclein, a protein integral to Parkinson's disease. Scientists have long thought the protein occurs in healthy cells as a single randomly coiled chain that resembles a writhing snake. Yet an innovative approach has shown that it has a radically different shape in healthy cells than previously thought. Writing in the September 1, 2011, issue of Nature, a research team led by Dennis Selkoe, the Vincent and Stella Coates Professor of Neurologic Diseases at Brigham and Women's Hospital and Harvard Medical School, reports that the protein's structure is orderly and sophisticated. This finding challenges existing disease paradigms and could suggest a new therapeutic approach.

Selkoe's team began its investigation by asking whether techniques used to probe the protein's clustering behavior might be overlooking important aspects of the protein's natural biology. So they designed new experiments to probe alpha-synuclein's behavior.

The initial data took them by surprise. There were no single isolated chains of alpha-synuclein. Instead, the data suggested that cells package four alpha-synuclein chains together as a tetrameric unit. The team confirmed this finding, showing that the unit consists of alpha-synuclein chains that have orderly twists.

In addition to providing new lines of therapeutic inquiry, the discovery of the folded tetramers should help labs shed light on the function of alpha-synuclein in healthy cells.

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