Enhanced access to the human phosphoproteome with genetically encoded phosphothreonine

Jack M. Moen, Kyle Mohler, Svetlana Rogulina, Xiaojian Shi, Hongying Shen and Jesse Rinehart ()
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Jack M. Moen: Yale School of Medicine
Kyle Mohler: Yale School of Medicine
Svetlana Rogulina: Yale School of Medicine
Xiaojian Shi: Yale School of Medicine
Hongying Shen: Yale School of Medicine
Jesse Rinehart: Yale School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Protein phosphorylation is a ubiquitous post-translational modification used to regulate cellular processes and proteome architecture by modulating protein-protein interactions. The identification of phosphorylation events through proteomic surveillance has dramatically outpaced our capacity for functional assignment using traditional strategies, which often require knowledge of the upstream kinase a priori. The development of phospho-amino-acid-specific orthogonal translation systems, evolutionarily divergent aminoacyl-tRNA synthetase and tRNA pairs that enable co-translational insertion of a phospho-amino acids, has rapidly improved our ability to assess the physiological function of phosphorylation by providing kinase-independent methods of phosphoprotein production. Despite this utility, broad deployment has been hindered by technical limitations and an inability to reconstruct complex phopho-regulatory networks. Here, we address these challenges by optimizing genetically encoded phosphothreonine translation to characterize phospho-dependent kinase activation mechanisms and, subsequently, develop a multi-level protein interaction platform to directly assess the overlap of kinase and phospho-binding protein substrate networks with phosphosite-level resolution.

Date: 2022
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DOI: 10.1038/s41467-022-34980-5

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