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

• Published in: Nature chemistry Vol. 9; no. 9; pp. 874 - 881
• Main Authors: Stöhr, Jan, Wu, Haifan, Nick, Mimi, Wu, Yibing, Bhate, Manasi, Condello, Carlo, Johnson, Noah, Rodgers, Jeffrey, Lemmin, Thomas, Acharya, Srabasti, Becker, Julia, Robinson, Kathleen, Kelly, Mark J. S., Gai, Feng, Stubbs, Gerald, Prusiner, Stanley B., DeGrado, William F.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2017; Nature Publishing Group
• Subjects: 631/378/1689/364; 631/45/460; 639/638/45/470/2284; 639/638/45/56; Agglomeration; Aggregation behavior; Alzheimer's disease; Amyloid; Analytical Chemistry; Animal models; Beta rays; Binding; Binding Sites; Biochemistry; Cells - drug effects; Cells - metabolism; Chemistry; Chemistry/Food Science; Deuterium; Dissection; Fibrils; Forming; HEK293 Cells; Humans; Hydrogen-deuterium exchange; Inorganic Chemistry; Microtubules - chemistry; Microtubules - metabolism; Neurodegenerative diseases; Neurological diseases; NMR; Nuclear magnetic resonance; Nuclei (cytology); Organic Chemistry; Peptide Fragments - chemistry; Peptide Fragments - pharmacology; Peptides; Physical Chemistry; Protein Aggregates - drug effects; Protein Aggregation, Pathological; Residues; Tau protein; tau Proteins - chemistry; tau Proteins - metabolism
• ISSN: 1755-4330; 1755-4349
• DOI: 10.1038/nchem.2754

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 tau 244–372 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 tau 244–372 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 tau 244–372 in cells is packaged in a remarkably small peptide. The self-propagation of misfolded conformations of tau occurs in neurodegenerative diseases, including Alzheimer's disease. The microtubule-binding region, tau 244-372 , reproduces much of the aggregation behaviour of tau in cells and animal models. Now, it has been shown that a 31-residue peptide from tau's R3 domain forms a cross-β conformation that efficiently seeds aggregation of tau 244-372 in cells.