MIT Chemists Determine Structure of Tau Protein’s Fuzzy Coat

MIT chemists determined the structure of the fuzzy coat surrounding Tau proteins. Using nuclear magnetic resonance (NMR) spectroscopy, they deciphered the structure of these disordered segments, which play a key role in Tau’s interactions with other molecules. This finding may help scientists develop drugs to prevent Tau buildup linked to Alzheimer’s disease.

Tau Protein Structure and Role in Neurodegenerative Disease

Tau proteins are crucial for stabilizing microtubules within healthy brain cells, but become problematic in neurodegenerative diseases like Alzheimer’s and frontotemporal dementia. When altered, these proteins clump together, forming tangles composed of a rigid core surrounded by approximately 80% disordered segments termed a “fuzzy coat.” Researchers discovered this fuzzy coat dictates how Tau interacts with other molecules, impacting disease progression and making it a key target for potential therapies. Measurements showed the fuzzy coat contains regions of intermediate mobility surrounding the rigid core, with the most dynamic segments rich in the amino acid proline located in the outermost layer.

This detailed understanding of protein dynamics suggests normal Tau proteins likely add to the ends of existing filaments, lengthening them, and provides insight into the mechanism of tangle formation.

NMR Spectroscopy Deciphers Tau Fibril Fuzzy Coat Structure

Researchers utilized nuclear magnetic resonance (NMR) spectroscopy to analyze the entire Tau protein, including the previously overlooked “fuzzy coat,” by developing techniques to measure magnetization transfer between rigid and mobile amino acids. This innovative approach tracked magnetization from rigid sections to floppy segments, estimating the proximity between them and revealing degrees of movement within the fuzzy coat itself. Findings indicated the Tau protein’s structure resembled layered burrito, with the rigid core surrounded by regions of intermediate and high mobility.

Measurements showed the outermost layer of the fuzzy coat was highly dynamic and rich in proline, an amino acid previously believed to be immobilized; instead, researchers found these proline-rich regions were repelled by the positively charged core. This detailed analysis could inform drug development aimed at disrupting Tau buildup.

Proton Magnetization Tracks Dynamics Within Tau Proteins

This innovative technique allowed estimation of the proximity between rigid and floppy segments, revealing a layered structure with three distinct mobility categories. These positively charged proline regions exhibited repulsion from the core’s positive charges, influencing overall Tau structure. Understanding these protein dynamics is crucial, as misfolded Tau is thought to act as a template, prompting normal proteins to assemble into the longer fibrils characteristic of Alzheimer’s disease; the fuzzy coat’s structure suggests addition to the fibril ends is more likely.

Fuzzy Coat Structure Influences Tau Fibril Assembly Mechanism

This suggests repulsion between positive charges in proline-rich regions and those forming the core, influencing overall structure. The Tau protein’s structure, resembling layered burrito, offers insights into fibril assembly, with the fuzzy coat wrapping the rigid core. Understanding these dynamics could enable the development of drugs designed to penetrate and disrupt the fuzzy coat, potentially preventing Tau buildup associated with Alzheimer’s and other neurodegenerative diseases.