Researchers at Yale University have obtained the clearest picture to date of tau protein’s solution-phase structure (J. Am. Chem. Soc., DOI: 10.1021/ja305206m). Tau, a macromolecule that aggregates and forms fibrils inside the neurons of Alzheimer’s patients, has been structurally investigated before. But now, using single-molecule fluorescence resonance energy transfer (FRET), Shana Elbaum-Garfinkle and Elizabeth Rhoades have made measurements on individual tau proteins rather than on large ensembles of them. Not only has the approach yielded a more detailed model of the native tau structure, says Jeff Kuret, a biochemist at Ohio State University, it has also provided “new insight into the conformational changes that likely precede tau aggregation.” That’s because Elbaum-Garfinkle and Rhoades also mapped tau’s structure when the protein was bound to heparin, a polyanion known to induce formation of tau aggregates. The researchers observed that in the presence of heparin, tau’s end segments sever long-range contact with one another and that one of the protein’s inner segments, called the microtubule-binding region, compresses. Designing drugs to stabilize tau and prevent these structural changes might be one disease-fighting strategy, the researchers suggest.