Taking a wider look at tau modifications

Semisynthesis aids study of posttranslational modifications to key Alzheimer’s protein

by Stu Borman
May 14, 2018 | APPEARED IN VOLUME 96, ISSUE 20


Credit: Adapted from J. Am. Chem. Soc.
The new semisynthetic method combines five tau segments: a bacterially expressed N-terminal region (blue); a three-part microtubule-binding domain (green, red, and gold); and a C-terminal segment (black). Numbers are amino acid positions in tau’s 441-residue sequence.

In the body, tau protein regulates nerve cell growth, nerve signal transmission, and the function of cytoskeletal components called microtubules. But it can also misfold, ending up in aggregates called neurofibrillary tangles in the brains of Alzheimer’s disease patients, making tau a diagnostic and therapeutic target.

Cells modify tau extensively by adding a range of extra chemical groups, called posttranslational modifications (PTMs), to the protein. But studies of these modifications up to now have focused primarily on one type of PTM—phosphorylation—in one part of tau—its C-terminal region. So tau’s PTM code, how the modifications affect tau’s behavior and aggregation potential, is mostly unknown.

After three years of effort, Hilal A. Lashuel and Mahmood Haj-Yahya at the Swiss Federal Institute of Technology, Lausanne, have developed a tau semisynthesis that could open a wider window on the protein’s PTM code (J. Am. Chem. Soc. 2018, DOI: 10.1021/jacs.8b02668).

They synthesized four fragments that make up the protein’s C-terminal and microtubule-binding regions, areas with tau’s most significant PTMs. They then used ligation reactions to combine these synthetic segments and a bacterially expressed N-terminal fragment to yield full-length tau with a completely native sequence.

The researchers can modify each synthetic domain with one or more PTMs before assembling the full protein. Using this method, they showed that acetylation at lysine 280 in the microtubule-binding domain enhances tau aggregation, implicating that PTM as a possible drug target.

“It’s a tour de force of semisynthesis and clearly an advance in the field of tau research,” says tau PTM specialist Christian P. R. Hackenberger of Humboldt University of Berlin.


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