Abstract
Rational design of peptide vaccines becomes important for the treatment of some diseases such as Alzheimer’s disease (AD) and related disorders. In this study, as part of a larger effort to explore correlations of structure and activity, we attempt to characterize the doubly phosphorylated chimeric peptide vaccine targeting a hyperphosphorylated epitope of the Tau protein. The 28-mer linear chimeric peptide consists of the double phosphorylated B cell epitope Tau229-237[pThr231/pSer235] and the immunomodulatory T cell epitope Ag85B241-255 originating from the well-known antigen Ag85B of the Mycobacterium tuberculosis, linked by a four amino acid sequence -GPSL-. NMR chemical shift analysis of our construct demonstrated that the synthesized peptide is essentially unfolded with a tendency to form a β-turn due to the linker. In conclusion, the -GPSL- unit presumably connects the two parts of the vaccine without transferring any structural information from one part to the other. Therefore, the double phosphorylated epitope of the Tau peptide is flexible and accessible.
Highlights
The conformation of a peptide or protein can be relevant to its stability and function
The peptide vaccine (Figure 1) comprised of 28 amino acids can be divided in three sections, the immunomodulatory T cell epitope Ag85B241-255 from Mycobacterium tuberculosis, the four amino acid linker sequence -GPSL, and the B cell epitope Tau229-237[pThr231/pSer235]
The peptide was synthesized by standard Fmoc-chemistry and was post-synthetically phosphorylated using phosphoramidite
Summary
The conformation of a peptide or protein can be relevant to its stability and function. To understand the relation between structure and function of peptides, it is necessary to consider folding initiation sites such as β-hairpin motifs [1] as well as α-helical and β-sheet like structures. It should be taken into account that medium-range peptides commonly exist in solution as complex mixtures of conformers of similar energies and correlation times. This inherent inhomogeneity often renders them difficult to study and determine specific interactions through the space associated with certain tertiary structural elements [2]. NMR analysis becomes a useful tool for the study of local conformational preferences that encode biological functions [11,12,13]
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