The microtubule-associated protein tau is extensively modified with O-linked N-acetylglucosamine.
Tau is a family of phosphoproteins that are important in modulating microtubule stability in neurons. In Alzheimer's disease tau is abnormally hyperphosphorylated, no longer binds microtubules, and self-assembles to form paired helical filaments that likely contribute to neuron death. Here we demonstrate that normal bovine tau is multiply modified by Ser(Thr)-O-linked N-acetylglucosamine, a dynamic and abundant post-translational modification that is often reciprocal to Ser(Thr)-phosphorylation. O-GlcNAcylation of tau was demonstrated by blotting with succinylated wheat germ agglutinin and by probing with bovine milk beta(1,4)galactosyltransferase. Structural analyses confirm the linkage and the saccharide structure. Tau splicing variants are multiply O-GlcNAcylated at similar sites, with an average stoichiometry of greater than 4 mol of O-linked N-acetylglucosamine/mol of tau. However, the number of sites occupied appears to be greater than 12, suggesting substoichiometric occupancy at any given site. A similar relationship between average stoichiometry and site-occupancy has also been described for the phosphorylation of tau. Site-specific or stoichiometric changes in O-GlcNAcylation may not only modulate tau function but may also play a role in the formation of paired helical filaments.
Arnold
C S
CS
Department of Biochemistry and Molecular Genetics, Schools of Medicine and Dentistry, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. GWHART@BMG.BHS.UAB.EDU
Johnson
G V
GV
Cole
R N
RN
Dong
D L
DL
Lee
M
M
Hart
G W
GW
D000117:Acetylglucosamine / Q000737:chemistry*; D000595:Amino Acid Sequence; D000818:Animals; D001923:Brain Chemistry; D002417:Cattle; D005700:Galactosyltransferases / Q000737:chemistry; D006031:Glycosylation; D008969:Molecular Sequence Data; D010766:Phosphorylation; D016875:tau Proteins / Q000737:chemistry*
D016875:tau Proteins; D005700:Galactosyltransferases; D000117:Acetylglucosamine