MIT chemists determine the structure of the fuzzy coat that surrounds Tau proteins

(Press-News.org) One of the hallmarks of Alzheimer’s disease is the clumping of proteins called Tau, which form tangled fibrils in the brain. The more severe the clumping, the more advanced the disease is.

The Tau protein, which has also been linked to many other neurodegenerative diseases, is unstructured in its normal state, but in the pathological state it consists of a well-ordered rigid core surrounded by floppy segments. These disordered segments form a “fuzzy coat” that helps determine how Tau interacts with other molecules.

MIT chemists have now shown, for the first time, they can use nuclear magnetic resonance (NMR) spectroscopy to decipher the structure of this fuzzy coat. They hope their findings will aid efforts to develop drugs that interfere with Tau buildup in the brain.

“If you want to disaggregate these Tau fibrils with small-molecule drugs, then these drugs have to penetrate this fuzzy coat,” says Mei Hong, an MIT professor of chemistry and the senior author of the new study. “That would be an important future endeavor.”

MIT graduate student Jia Yi Zhang is the lead author of the paper, which appears today in the Journal of the American Chemical Society. Former MIT postdoc Aurelio Dregni is also an author of the paper.

Analyzing the fuzzy coat

In a healthy brain, Tau proteins help to stabilize microtubules, which give cells their structure. However, when Tau proteins become misfolded or otherwise altered, they form clumps that contribute to neurodegenerative diseases such as Alzheimer’s and frontotemporal dementia.

Determining the structure of the Tau tangles has been difficult because so much of the protein — about 80 percent — is found in the fuzzy coat, which tends to be highly disordered.

This fuzzy coat surrounds a rigid inner core that is made from folded protein strands known as beta sheets. Hong and her colleagues have previously analyzed the structure of the core in a particular Tau fibril using NMR, which can reveal the structures of molecules by measuring the magnetic properties of atomic nuclei within the molecules.

Until now, most researchers had overlooked Tau’s fuzzy coat and focused on the rigid core of the fibrils because those disordered segments change their structures so often that standard structure characterization techniques such as cryoelectron microscopy and X-ray crystallography can’t capture them.

However, in the new study, the researchers developed NMR techniques that allowed them to study the entire Tau protein. In one experiment, they were able to magnetize protons within the most rigid amino acids, then measure how long it took for the magnetization to be transferred to the mobile amino acids. This allowed them to track the magnetization as it traveled from rigid regions to floppy segments, and vice versa.

Using this approach, the researchers could estimate the proximity between the rigid and mobile segments. They complemented this experiment by measuring the different degrees of movement of the amino acids in the fuzzy coat.

“We have now developed an NMR-based technology to examine the fuzzy coat of a full-length Tau fibril, allowing us to capture both the dynamic regions and the rigid core,” Hong says.

Protein dynamics

For this particular fibril, the researchers showed that the overall structure of the Tau protein, which contains about 10 different domains, somewhat resembles a burrito, with several layers of the fuzzy coat wrapped around the rigid core.

Based on their measurements of protein dynamics, the researchers found that these segments fell into three categories. The rigid core of the fibril was surrounded by protein regions with intermediate mobility, whereas the most dynamic segments were found in the outermost layer.

The most dynamic segments of the fuzzy coat are rich in the amino acid proline. In the protein sequence, these prolines are near the amino acids that form the rigid core, and were previously thought to be partially immobilized. Instead, they are highly mobile, indicating that these positively charged proline-rich regions are repelled by the positive charges of the amino acids that form the rigid core.

This structural model gives insight into how Tau proteins form tangles in the brain, Hong says. Similar to how prions trigger healthy proteins to misfold in the brain, it is believed that misfolded Tau proteins latch onto normal Tau proteins and act as a template that induces them to adopt the abnormal structure.

In principle, these normal Tau proteins could add to the ends of existing short filaments or pile onto the sides. The fact that the fuzzy coat wraps around the rigid core indicates that normal Tau proteins more likely add onto the ends of the filaments to generate longer fibrils.

The researchers now plan to explore whether they can stimulate normal Tau proteins to assemble into the type of fibrils seen in Alzheimer’s disease, using misfolded Tau proteins from Alzheimer’s patients as a template.

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The research was funded by the National Institutes of Health.

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