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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cells / drug effects*
  • Cells / metabolism
  • HEK293 Cells
  • Humans
  • Microtubules / chemistry*
  • Microtubules / metabolism
  • Peptide Fragments / chemistry*
  • Peptide Fragments / pharmacology*
  • Protein Aggregates / drug effects*
  • Protein Aggregation, Pathological*
  • tau Proteins / chemistry*
  • tau Proteins / metabolism


  • Peptide Fragments
  • Protein Aggregates
  • tau Proteins