Development and Application of Proteomic Technologies for the Analysis of Post-Translational Modifications




Sprung, Robert William, Jr.

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Post-translational modifications represent a rapid and dynamic means for diversifying the chemistry of the ~20 ribosomally coded amino acids. As such, they provide an ideal mechanism for promoting cellular adaptability by facilitating the tuning of protein interactions and functions in response to changing environmental conditions. Despite their fundamental importance in regulating cellular functions and their wide implications in physiology, efficient means for the detection, enrichment and identification of proteins bearing specific modifications are lacking for most modifications. The availability of such methods would constitute invaluable tools supporting efforts to better understand the essential regulatory roles of modifications and the means by which aberrant modifications result in the onset and progression of disease. Towards this end, my dissertation describes the development and application of novel methods for the proteomic analysis of proteins bearing known modifications, including O-GlcNAc, lysine acetylation and methyl esterification. The identification of known targets of the modifications support some of the current ideas regarding their potential impact and serve as a means of validating the methods. More importantly, the identification of novel targets for the modifications challenges some currently held concepts, in particular regarding the relatively limited regulatory roles associated with lysine acetylation. In addition, the unparalleled power of proteomics as a screening strategy is demonstrated through compelling evidence of the existence of novel lysine acylations in vivo with respect to propionylation and butyrylation. Together, the methods described in this dissertation and the datasets generated embody powerful platforms and rich resources for the ongoing exploration of the fundamental contributions of post-translational modifications to the regulation of biological processes.

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