Towards chemical synthesis of proteins with post-translational modifications

Abstract

Recently, there is an increasing demand to study the protein post-translational modifications (PTMs) in understanding the increase in complexity from the level of the genome to the proteome. The proteins carrying homogenous and defined PTM structures are very difficult to be obtained using biologically controlled methods; thus to correlate the structure of PTM to its function is a difficult task. In this regard, chemical synthesis of proteins will make important contribution to the provision of PTM proteins with high homogeneity and the defined structure. In addition, the chemical synthesis will allow for the generation of new bio-macromolecules with altered structures, including the incorporation of unnatural elements, to create new functions. Our laboratory has been trying to develop methods and strategies to chemically synthesize proteins with glycosylation and phosphorylation. One method developed is Serine/Threonine Ligation, in which one side chain unprotected peptide segment with a C-terminal salicylaldehyde (SAL) ester reacts with another side chain unprotected peptide segment with N-terminal serine or threonine to form an N,Obenzylidene acetal intermediate, followed by acidolysis to reveal the natural Xaa-Ser/Thr linkage.1 In this presentation, the recent applications of STL in the synthesis of proteins with post-translational modifications will be discussed. This work was supported by the Research Grants Council-General Research Fund of Hong Kong.