Abstract
Protein phosphorylation is essential for regulating cellular activities by modifying substrates at specific residues, which frequently interact with proteins containing phosphoprotein-binding domains (PPBDs) to propagate the phosphorylation signaling into downstream pathways. Although massive phosphorylation sites (p-sites) have been reported, most of their interacting PPBDs are unknown. Here, we collected 4458 known PPBD-specific binding p-sites (PBSs), considerably improved our previously developed group-based prediction system (GPS) algorithm, and implemented a deep learning plus transfer learning strategy for model training. Then, we developed a new online service named GPS-PBS, which can hierarchically predict PBSs of 122 single PPBD clusters belonging to two groups and 16 families. By comparison, GPS-PBS achieved a highly competitive accuracy against other existing tools. Using GPS-PBS, we predicted 371,018 mammalian p-sites that potentially interact with at least one PPBD, and revealed that various PPBD-containing proteins (PPCPs) and protein kinases (PKs) can simultaneously regulate the same p-sites to orchestrate important pathways, such as the PI3K-Akt signaling pathway. Taken together, we anticipate GPS-PBS can be a great help for further dissecting phosphorylation signaling networks.
Highlights
In eukaryotes, protein phosphorylation is by far the most important and widespread post-translational modification that mainly occurs on specific serine (S), threonine (T) or tyrosine (Y)residues in protein substrates, and orchestrates a variety of biological processes including signaling transduction, cell cycle/proliferation, autophagy and metabolism [1,2,3,4]
According to the classification information of PPBD-containing proteins (PPCPs) [28], the PBSs under the pS/pT group were further classified into 12 families, including 14-3-3, BRCA1 carboxyl-terminal (BRCT), forkhead-associated (FHA), kinase-inducible domain interacting domain (KIX), polo-box domain (PBD), WW, Mad homology 2 (MH2), WD40, Interferon-regulatory factor 3 (IRF3), Guanylate kinase (GK), Arrestin and leucine-rich repeat (LRR), whereas the dataset of the pY group was categorized into four families, including Src homology 2 (SH2), phosphotyrosine-binding (PTB), protein kinase C conserved region 2 (C2), and Hakai phospho-tyrosine binding domain (HYB)
Besides the group and family levels, we considered the classification of PBSs at the single phosphoprotein-binding domains (PPBDs) level, and PBSs recognized by orthologous PPBDs conserved in different species were merged into the same cluster of single PPBDs
Summary
Residues in protein substrates, and orchestrates a variety of biological processes including signaling transduction, cell cycle/proliferation, autophagy and metabolism [1,2,3,4]. Numerous proteins containing phosphoprotein-binding domains (PPBDs) can recognize and bind phosphoserine (pS), phosphothreonine (pT) or phosphotyrosine (pY) residues in specific substrates as “readers”, which dictate the phosphorylation signaling events delivered from “writers”, namely, protein kinases (PKs), and accurately propagate signals into downstream pathways [5,6,7]. The identification of PPBD-specific binding p-sites (PBSs) is fundamental for revealing dynamic phosphorylation signaling networks. A variety of experimental methods, such as including phage display, one-peptide/one-pin type techniques, alanine-scanning mutagenesis of the protein substrates, and oriented peptide library screening (OPLS), were established to identify phosphorylation-mediated interactions (PMIs) and/or pinpoint the exact
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