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Life Sciences seminar: "The expanding landscape of human protein phosphorylation”

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Location: GLT2, Gibbet Hill campus

Professor Claire Eyers, University of Liverpool

"The expanding landscape of human protein phosphorylation” 

Protein phosphorylation is a ubiquitous post-translational modification (PTM) that regulates all aspects of life. To date, investigation of human phosphorylation-mediated cell signalling has focussed on canonical phosphorylation of serine (Ser), threonine (Thr) and tyrosine (Tyr) residues. However, mounting evidence suggests that phosphorylation of histidine also plays a central role in regulating human cell biology. Biochemical and phosphoproteomics workflows rely on acidic conditions or elevated temperatures for analysis, which are incompatible with the analysis of acid-labile phosphorylation such as histidine. Consequently, the extent of ‘non-canonical’ phosphorylation in humans and other vertebrates is likely to be severely under-estimated. We have developed an Unbiased Phosphopeptide enrichment strategy based on Strong Anion Exchange (SAX) chromatography (UPAX), which permits enrichment of acid-labile phosphopeptides for characterisation by mass spectrometry. This approach has allowed us to identify extensive and positional phosphorylation patterns on histidine, arginine, lysine, aspartate and glutamate in human cell extracts. Remarkably, the extent of phosphorylation on individual non-canonical residues vastly exceeds that of basal phosphotyrosine, and in some cases phosphothreonine. Our study reveals the previously unappreciated diversity of protein phosphorylation in human cells, and opens up avenues for exploring roles of acid-labile phosphorylation in any proteome using mass spectrometry.

 

Our recent advances in the application of capillary electrophoresis (CESI) in combination with high resolution MS to explore combinatorial protein modifications on the same polypeptide chain and thus proteoform heterogeneity at the level of intact proteins will also be discussed

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