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Nat Chem. 2017 Sep;9(9):874-881. doi: 10.1038/nchem.2754. Epub 2017 Apr 3.

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

Author information

1
Institute for Neurodegenerative Diseases, University of California, San Francisco, California 94143, USA.
2
Department of Neurology, University of California, San Francisco, California 94143, USA.
3
Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143, USA.
4
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
5
Department of Biological Sciences and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37235, USA.
6
Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143, USA.

Abstract

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.

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