3 years ago

A 31-residue peptide induces aggregation of tau's microtubule-binding region in cells

A 31-residue peptide induces aggregation of tau's microtubule-binding region in cells
Thomas Lemmin, Jeffrey Rodgers, Stanley B. Prusiner, Mark J. S. Kelly, Yibing Wu, Mimi Nick, Srabasti Acharya, Gerald Stubbs, Julia Becker, Haifan Wu, Feng Gai, Carlo Condello, Jan Stöhr, Kathleen Robinson, Noah Johnson, William F. DeGrado, Manasi Bhate
The self-propagation of misfolded conformations of tau underlies neurodegenerative diseases, including Alzheimer's. There is considerable interest in discovering the minimal sequence and active conformational nucleus that defines this self-propagating event. The microtubule-binding region, spanning residues 244–372, reproduces much of the aggregation behaviour of tau in cells and animal models. Further dissection of the amyloid-forming region to a hexapeptide from the third microtubule-binding repeat resulted in a peptide that rapidly forms fibrils in vitro. We show that this peptide lacks the ability to seed aggregation of tau244–372 in cells. However, as the hexapeptide is gradually extended to 31 residues, the peptides aggregate more slowly and gain potent activity to induce aggregation of tau244–372 in cells. X-ray fibre diffraction, hydrogen–deuterium exchange and solid-state NMR studies map the beta-forming region to a 25-residue sequence. Thus, the nucleus for self-propagating aggregation of tau244–372 in cells is packaged in a remarkably small peptide.

Publisher URL: http://dx.doi.org/10.1038/nchem.2754

DOI: 10.1038/nchem.2754

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