N-terminal fragments of tau inhibit full-length tau polymerization in vitro.
The polymerization of the microtubule-associated protein, tau, into insoluble filaments is a common thread in Alzheimer's disease and in a variety of frontotemporal dementias. The conformational change required for tau to transition from an extended monomeric state to a filamentous state with a high beta-sheet content involves the extreme N-terminus coming into contact with distal portions of the molecule; however, these exact interactions are incompletely understood. Here we report that a construct representing amino acids 1-196 (Tau196), which itself does not polymerize, inhibits polymerization of full-length tau (hTau40) in vitro. In addition, we trace the inhibitory effect of Tau196 to amino acids 18-42 of the construct. We also provide evidence that the N-terminal tau fragments require a specific C-terminal region of tau (residues 392-421) to exert their inhibitory effect. The fragments are most effective at inhibiting polymerization when present during the initial 5 min; they remain in the soluble fraction of the polymerization reaction, and they increase the amount of soluble hTau40. The fragments also reduce the number and average length of filaments that are formed. Taken together, these results suggest that the N-terminal tau fragments inhibit hTau40 polymerization by interacting with a specific C-terminal sequence, thereby stabilizing a soluble conformation of tau.
Horowitz
Peleg M
PM
Department of Cell and Molecular Biology, Northwestern University, Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, Illinois 60611-3008, USA. p-horowitz@md.northwestern.edu
LaPointe
Nichole
N
Guillozet-Bongaarts
Angela L
AL
Berry
Robert W
RW
Binder
Lester I
LI
D000595:Amino Acid Sequence; D016718:Arachidonic Acid / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*
D010446:Peptide Fragments; D016875:tau Proteins; D016718:Arachidonic Acid