title: Lysine methylation is an endogenous post-translational modification of tau protein in human brain and a modulator of aggregation propensity.
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 propensity was greatly attenuated at both nucleation and extension steps. These data establish lysine methylation 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.
authors.affiliation: *Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine, Columbus, OH 43210, U.S.A.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Funk
authors.affiliation: †Department of Anatomy and Neurobiology, Molecular and Structural Biology Program, Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201, U.S.A.
authors.forename: Stefani N
authors.initials: SN
authors.lastname: Thomas
authors.affiliation: *Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine, Columbus, OH 43210, U.S.A.
authors.forename: Kelsey N
authors.initials: KN
authors.lastname: Schafer
authors.affiliation: *Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine, Columbus, OH 43210, U.S.A.
authors.forename: Grace L
authors.initials: GL
authors.lastname: Cooper
authors.affiliation: †Department of Anatomy and Neurobiology, Molecular and Structural Biology Program, Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201, U.S.A.
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Liao
authors.affiliation: †Department of Anatomy and Neurobiology, Molecular and Structural Biology Program, Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201, U.S.A.
authors.forename: David J
authors.initials: DJ
authors.lastname: Clark
authors.affiliation: †Department of Anatomy and Neurobiology, Molecular and Structural Biology Program, Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201, U.S.A.
authors.forename: Austin J
authors.initials: AJ
authors.lastname: Yang
authors.affiliation: *Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine, Columbus, OH 43210, U.S.A.
authors.forename: Jeff
authors.initials: J
authors.lastname: Kuret
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008297:Male; D008745:Methylation; D008870:Microtubules / Q000378:metabolism; D008875:Middle Aged; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D020836:Protein Structure, Quaternary; D053719:Tandem Mass Spectrometry; D014404:Tubulin / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D014404:Tubulin; D016875:tau Proteins; D008239:Lysine