Intrinsic Disorder in Proteins Associated with Oxidative Stress-induced JNK Signaling

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C-jun N-terminal Kinase (JNK) Signaling Pathway, Oxidative Stress, Intrinsically Disordered Proteins, Intrinsically Disordered Protein Regions, Molecular Recognition Features, Posttranslational Modifications, Short Linear Motifs

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The c-Jun N-terminal kinase (JNK) signaling cascade is a mitogen-activated protein kinase (MAPK) signaling pathway that can be activated in response to a wide range of environmental stimuli. Based on the type, degree, and duration of the stimulus, the JNK signaling cascade dictates the fate of the cell by influencing gene expression through its substrate transcription factors. Oxidative stress is a result of a disturbance in the pro-oxidant/antioxidant homeostasis of the cell and is associated with a large number of diseases, such as neurodegenerative disorders, cancer, diabetes, cardiovascular diseases, and disorders of the immune system, where it activates the JNK signaling pathway. Among different biological roles ascribed to the intrinsically disordered proteins (IDPs) and hybrid proteins containing ordered domains and intrinsically disordered protein regions (IDPRs) are signaling hub functions, as intrinsic disorder allows proteins to undertake multiple interactions, each with a different consequence. In order to ensure precise signaling, the cellular abundance of IDPs is highly regulated, and mutations or changes in abundance of IDPs/IDPRs are often associated with disease. In this study, we have used a combination of six disorder predictors to evaluate the presence of intrinsic disorder in proteins of the oxidative stress-induced JNK signaling cascade, and as per our findings, none of the 18 proteins involved in this pathway are ordered. The highest level of intrinsic disorder was observed in the scaffold proteins, JIP1, JIP2, JIP3; dual specificity phosphatases, MKP5, MKP7; 14-3-3ζ and transcription factor c-Jun. The MAP3Ks, MAP2Ks, MAPKs, TRAFs, and thioredoxin were the proteins that were predicted to be moderately disordered. Furthermore, to characterize the predicted IDPs/IDPRs in the proteins of the JNK signaling cascade, we identified the molecular recognition features (MoRFs), posttranslational modification (PTM) sites, and short linear motifs (SLiMs) associated with the disordered regions. These findings will serve as a foundation for experimental characterization of disordered regions in these proteins, which represents a crucial step for a better understanding of the roles of IDPRs in diseases associated with this important pathway.

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Cellular and Molecular Life Sciences, v. 79, art. 202