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Tyrosine- versus serine-phosphorylation leads to conformational changes in a synthetic tau peptide
H Fabian1, L Otvos, G I Szendrei
1Institute for Biochemistry, Humboldt University Berlin, Germany.
Abstract:
One of the major immunodominant epitopes of the paired helical filaments (PHF) of Alzheimer's disease is the peptide sequence GAEIVYKSPVVSGD (T3), comprising amino acids 389-402 of the microtubule-associated protein, tau, when it is phosphorylated at the first serine residue. While the corresponding anti-PHF monoclonal antibody recognizes the peptide phosphorylated at either serine, it does not recognize the tyrosine-phosphorylated peptide. Here we describe the effect of serine- versus tyrosine-phosphorylation on the conformation of a synthetic tau peptide. While adding a phosphate to the serine residue has practically no impact on the structure of the non-phosphorylated peptide, phosphorylation of the tyrosine results in considerable conformational changes.
Insights
Phosphorylation of tau peptide impacts Alzheimer's disease (AD) pathology. Serine phosphorylation has minimal effect, while tyrosine phosphorylation significantly alters tau peptide conformation, affecting antibody binding in AD.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Paired helical filaments (PHF) in Alzheimer's disease (AD) feature immunodominant tau epitopes.
- The T3 peptide (amino acids 389-402 of tau) is a major epitope when phosphorylated at serine.
- Anti-PHF monoclonal antibodies recognize serine-phosphorylated T3 but not tyrosine-phosphorylated T3.
Purpose of the Study:
- To investigate the conformational effects of serine versus tyrosine phosphorylation on a synthetic tau peptide.
- To understand how differential phosphorylation impacts the recognition by anti-PHF antibodies.
Main Methods:
- Synthesis of a tau peptide (T3) corresponding to amino acids 389-402.
- Phosphorylation of the synthetic tau peptide at serine and tyrosine residues.
- Conformational analysis of non-phosphorylated, serine-phosphorylated, and tyrosine-phosphorylated tau peptides.
Main Results:
- Serine phosphorylation of the tau peptide resulted in negligible conformational changes compared to the non-phosphorylated peptide.
- Tyrosine phosphorylation induced significant conformational alterations in the synthetic tau peptide.
- These conformational changes likely explain the differential binding of anti-PHF monoclonal antibodies.
Conclusions:
- Differential phosphorylation of tau at serine and tyrosine residues has distinct effects on peptide conformation.
- Tyrosine phosphorylation-induced conformational changes may influence the immunogenicity and antibody recognition of tau in Alzheimer's disease.
- Understanding these structural modifications is crucial for developing targeted diagnostics and therapeutics for AD.