Early conformations of tau in disease

October 1, 2012 § Leave a comment

Simulated structure of tau in solution derived from experimental single molecule FRET measurements. MTBR stands for microtubule binding region. Image credit: Shana Elbaum-Garfinkle and Abhinav Nath

Tauopathies are neurodegenerative disorders in which a protein called tau forms insoluble tangles in the brain. In a recent paper in the Journal of the American Chemical Society, researchers looked into conformational changes early in the protein’s aggregation process and discovered that some critical physicochemical changes take place.

Tau is a microtubule-binding protein. It has a N-terminal domain that is unstructured, followed by a proline-rich region and then a C-terminal microtubule-binding domain. While the protein is largely unstructured in its native form, it takes on a highly ordered, β-sheet-rich structure in diseases such as Alzheimer’s and frontotemporal dementias.

How tau goes from an unstructured entity to a structured one in a disease has been a longstanding question. It’s been a hard question to answer because studying disordered proteins can be technically challenging.  Most methods require a certain amount of protein for detection purposes, but proteins like tau start to clump quickly at those amounts, making it very hard to get a step-by-step understanding of the aggregation mechanism.

To get a handle on the molecular details of tau aggregation, Shana Elbaum–Garfinkle and Elizabeth Rhoades at Yale University decided to use single-molecule Forster resonance energy transfer. Single-molecule FRET, explains Rhoades, allowed them to use amounts in their experiments that  “strongly disfavored aggregation, such that we could characterize the conformational changes associated with the initiation of aggregation without any signal complications arising from the presence of aggregates.”

In a test tube, tau can be made to form clumps that resemble those in patient brains by adding polyanionic compounds, such as heparin.  Elbaum–Garfinkle and Rhoades made FRET measurements on tau, with and without heparin, using multiple sets of labeling positions.

The investigators found that different domains of tau had distinct physicochemical and conformational properties that were connected to their relative structural disorder.  Their data indicated that in the presence of heparin tau seemed to let go of long-range interactions and compacted its microtubule-binding and proline-rich domains early on in its conversion to insoluble tangles.

Rhoades says the multiple labeling sites in their experiments allowed them to properly grasp how the normally disordered tau behaved in the initial stages of aggregation. “If we had used a single pair of labeling sites to study tau, we would have drawn entirely different conclusions about its behavior,” she says. 

Rhoades points out that the data are quite far removed from having therapeutic applications but they do “suggest that there are specific conformations associated with the initiation of aggregation of tau. Drugs that reduce or inhibit the population of these conformations may be an effective strategy for therapeutics.”

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