Cross-linking sites of the human tau protein, probed by reactions with human transglutaminase

S. N.Prasanna Murthy, James H. Wilson, Thomas J. Lukas, Jeff Kuret*, Laszlo Lorand

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

A portion of the neurofibrillary tangles of Alzheimer's disease has the characteristics of cross-linked protein. Because the principal component of these lesions is the microtubule-associated protein tau, and because a major source of cross-linking activity within neurons is supplied by tissue transglutaminase (TGase), it has been postulated that isopeptide bond formation is a major posttranslational modification leading to the formation of insoluble neurofibrillary tangles. Here we have mapped the sites on two isoforms of human tau protein (τ23 and τ-40) capable of participating in human TGase-mediated isopeptide bond formation. Using dansyl-labeled fluorescent probes, it was shown that eight Gln residues can function as amine acceptor residues, with two major sites being Gln351 and Gln424. In addition, 10 Lys residues were identified as amine donors, most of which are clustered adjacent to the microtubule-binding repeats of tau in regions known to be solvent accessible in filamentous tau. The distribution of amine donors correlated closely with that of Arg residues, suggesting a link between neighboring positive charge and the TGase selectivity for donor sites in the protein substrate. Apart from revealing the sites that can be cross- linked during the TGase-catalyzed assembly of tau filaments, the results suggest a topography for the tau monomers so assembled.

Original languageEnglish (US)
Pages (from-to)2607-2614
Number of pages8
JournalJournal of neurochemistry
Volume71
Issue number6
DOIs
StatePublished - Dec 1998

Keywords

  • Alzheimer's disease
  • Neurofibrillary tangles
  • Paired helical filament
  • Tau protein
  • Transglutaminase

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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