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Glycosylation and phosphorylation induce alternative structural conformations in tau's proline‐rich domain
Author(s) -
Brister Michael Angelo,
Bielska Agata A,
Zondlo Neal J
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.752.9
Subject(s) - glycosylation , phosphorylation , threonine , chemistry , serine , polyproline helix , biochemistry , circular dichroism , tau protein , peptide , stereochemistry , alzheimer's disease , medicine , disease , pathology
The microtubule‐associated protein tau is the primary constituent of neurofibrillary tangles, a pathological hallmark of Alzheimer's disease. In its diseased state, tau is phosphorylated on over 30 residues, many of which are alternatively modified by glycosylation by N‐acetylglucosamine (O‐GlcNAc) in tau's native state. We hypothesized that glycosylation of threonine and serine residues on tau peptides may induce a structural effect different from that of phosphorylation at these locations. We have employed a scheme for the synthesis of glycopeptides incorporating O‐GlcNAc and isolated O‐GlcNAcylated peptides derived from tau's proline‐rich domain. Furthermore, we have developed a functional group to mimic O‐GlcNAc modification (pseudo‐glycosylation). Phosphorylated, glycosylated, pseudo‐glycosylated and unmodified tau peptides were structurally characterized using circular dichroism and NMR. While phosphorylated sequences exhibited high propensity to form a type II polyproline helix, glycosylated and pseudo‐glycosylated peptides exhibited more flexible secondary structures. These findings suggest a structural role for tau modification by O‐GlcNAc. This project was supported by the Howard Hughes Medical Institute.