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Comparative posttranslational proteomic approaches for understanding development and degeneration


Cellular function is largely determined by posttranslational modification (PTM) of proteins that govern protein-protein interactions, protein-nucleic acid interaction, transcription, enzymatic activities, etc. Yet, identifying and determining the role of various PTM's in development and degeneration remains a daunting task. Among the many PTM's, glutamylation/deglutamylation was identified more than 30 years ago and involves the addition of glutamic acid residues branching from an encoded glutamic acid residue in an acidic region (deglutamylation is the removal of C-terminal primary sequence Glu residues or PTM Glu). Alpha tubulin was the first protein to be identified as being posttranslationally glutamylated which has since been found to regulate microtubule stability and ciliary function. However the identification of other proteins undergoing deglutamylation remains poorly defined. Using a mouse model of neurodegeneration that is deficient for a single deglutamylase, we utilized a direct comprehensive comparative proteomics approach and identified a predicted HMG box containing protein at the mitochondrion and show specific interaction of this protein with the deglutamylase. Furthermore, the affected cell type in this model shows an increase in oxidative damage of mtDNA indicating a potential role for deglutamylation in maintaining mtDNA integrity. Unlike glutamylation, phosphorylation is the most well studied PTM, however, the roles of most predicted phosphosites across the proteome have yet to be determined. Recent technological advances have dramatically improved phosphoproteomic approaches, yet the identification of critical phosphosites involved in maintaining pluripotent human ES cells has largely been underexplored. The developmental pathways controlling the maintenance of the undifferentiated state and the initiation of the earliest neurectodermal lineage were investigated using comparative total cellular phosphoproteomics. As one of the first reports of comprehensive phosphoproteomic profiling and analysis of hESCs, we have revealed a previously unknown role for JNK activity in maintaining the pluripotent state

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