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Phosphorylation plays a key role in the regulation of protein function. In addition to the extensively studied O-phosphorylation of serine, threonine, and tyrosine, emerging evidence suggests that the non-canonical phosphorylation of histidine, lysine, and arginine termed N-phosphorylation, exists widely in eukaryotes. At present, the study of N-phosphorylation is still in its infancy, and its regulatory role and specific biological functions in mammalian cells are still unknown. Here, we report the in silico analysis of the systematic biological significance of N-phosphorylated proteins in human cells. The protein structural and functional domain enrichment analysis revealed that N-phosphorylated proteins are rich in RNA recognition motif, nucleotide-binding and alpha-beta plait domains. The most commonly enriched biological pathway is the metabolism of RNA. Besides, arginine phosphorylated (pArg) proteins are highly related to DNA repair, while histidine phosphorylated (pHis) proteins may play a role in the regulation of the cell cycle, and lysine phosphorylated (pLys) proteins are linked to cellular stress response, intracellular signal transduction, and intracellular transport, which are of great significance for maintaining cell homeostasis. Protein-protein interaction (PPI) network analysis revealed important hub proteins (i.e., SRSF1, HNRNPA1, HNRNPC, SRSF7, HNRNPH1, SRSF2, SRSF11, HNRNPD, SRRM2 and YBX1) which are closely related to neoplasms, nervous system diseases, and virus infection and have potential as therapeutic targets. Those proteins with clinical significance are worthy of attention, and the rational considerations of N-phosphorylation in occurrence and progression of diseases might be beneficial for further translational applications. Copyright © 2022 Elsevier Ltd. All rights reserved.


Shanshan Wang, Yu Zong Chen, Songsen Fu, Yufen Zhao. In silico approaches uncovering the systematic function of N-phosphorylated proteins in human cells. Computers in biology and medicine. 2022 Dec;151(Pt A):106280

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PMID: 36375414

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