Qian Xuesen Collaborative Research Center of Astrochemistry and Space Life Sciences, Institute of Drug Discovery Technology, Ningbo University, Ningbo, 315211, China.
Qian Xuesen Collaborative Research Center of Astrochemistry and Space Life Sciences, Institute of Drug Discovery Technology, Ningbo University, Ningbo, 315211, China.
Comput Biol Med. 2022 Dec;151(Pt A):106280. doi: 10.1016/j.compbiomed.2022.106280. Epub 2022 Nov 2.
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.
磷酸化在蛋白质功能的调控中起着关键作用。除了广泛研究的丝氨酸、苏氨酸和酪氨酸的 O-磷酸化外，新出现的证据表明，组氨酸、赖氨酸和精氨酸的非典型磷酸化，即 N-磷酸化，在真核生物中广泛存在。目前，N-磷酸化的研究仍处于起步阶段，其在哺乳动物细胞中的调控作用和特定生物学功能尚不清楚。在这里，我们报告了在人类细胞中 N-磷酸化蛋白系统生物学意义的计算机分析。蛋白质结构和功能域富集分析表明，N-磷酸化蛋白富含 RNA 识别基序、核苷酸结合和α-β 折叠结构域。最常见的富集生物途径是 RNA 的代谢。此外，精氨酸磷酸化（pArg）蛋白与 DNA 修复高度相关，而组氨酸磷酸化（pHis）蛋白可能在细胞周期调控中发挥作用，赖氨酸磷酸化（pLys）蛋白与细胞应激反应、细胞内信号转导和细胞内运输有关，这对维持细胞内稳态具有重要意义。蛋白质-蛋白质相互作用（PPI）网络分析揭示了重要的枢纽蛋白（如 SRSF1、HNRNPA1、HNRNPC、SRSF7、HNRNPH1、SRSF2、SRSF11、HNRNPD、SRRM2 和 YBX1），它们与肿瘤、神经系统疾病和病毒感染密切相关，具有作为治疗靶点的潜力。那些具有临床意义的蛋白质值得关注，对疾病发生和进展中 N-磷酸化的合理考虑可能有助于进一步的转化应用。
