N-terminal fragments of tau inhibit full-length tau polymerization in vitro

Biochemistry. 2006 Oct 24;45(42):12859-66. doi: 10.1021/bi061325g.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Arachidonic Acid / metabolism
  • Arachidonic Acid / pharmacology
  • Binding Sites
  • Humans
  • Kinetics
  • Models, Molecular
  • Molecular Sequence Data
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology*
  • Protein Conformation
  • tau Proteins / antagonists & inhibitors*
  • tau Proteins / chemistry
  • tau Proteins / drug effects
  • tau Proteins / metabolism*

Substances

  • Peptide Fragments
  • tau Proteins
  • Arachidonic Acid