Lysine methylation is an endogenous post-translational modification of tau protein in human brain and a modulator of aggregation propensity

Kristen E. Funk, Stefani N. Thomas, Kelsey N. Schafer, Grace L. Cooper, Zhongping Liao, David J. Clark, Austin J. Yang, Jeff Kuret

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

In Alzheimer's disease, the microtubule-associated protein tau dissociates from the neuronal cytoskeleton and aggregates to form cytoplasmic inclusions. Although hyperphosphorylation of tau serine and threonine residues is an established trigger of tau misfunction and aggregation, tau modifications extend to lysine residues as well, raising the possibility that different modification signatures depress or promote aggregation propensity depending on site occupancy. To identify lysine residue modifications associated with normal tau function, soluble tau proteins isolated from four cognitively normal human brains were characterized by MS methods. The major detectable lysine modification was found to be methylation, which appeared in the form of mono- and di-methyl lysine residues distributed among at least 11 sites. Unlike tau phosphorylation sites, the frequency of lysine methylation was highest in the microtubule-binding repeat region that mediates both microtubule binding and homotypic interactions. When purified recombinant human tau was modified in vitro through reductive methylation, its ability to promote tubulin polymerization was retained, whereas its aggregation propensitywas greatly attenuated at both nucleation and extension steps. These data establish lysinemethylation as part of the normal tau post-translational modification signature in human brain, and suggest that it can function in part to protect against pathological tau aggregation.

Original languageEnglish (US)
Pages (from-to)77-88
Number of pages12
JournalBiochemical Journal
Volume462
Issue number1
DOIs
StatePublished - Jul 15 2014
Externally publishedYes

Keywords

  • Aggregation
  • Alzheimer's disease
  • Methylation
  • Microtubule
  • Post-translational modification
  • Tau protein

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