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Intrinsic disorder in proteins associated with oxidative stress-induced JNK signaling

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Abstract

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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Data availability

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

Abbreviations

Aβ:

Amyloid β

AD:

Alzheimer’s disease

AIDS:

Acquired immunodeficiency syndrome

ALS:

Amyotrophic lateral sclerosis

AP1:

Activator protein-1

ASK:

Apoptosis regulating kinase

ATF2:

Cyclic AMP-dependent transcription factor ATF-2

D2P2 :

Database of disordered protein predictions

DSP:

Dual specificity phosphatases

ELM:

Eukaryotic linear motif

ERK:

Extracellular signal-regulated kinases

IDP:

Intrinsically disordered protein

IDPR:

Intrinsically disordered protein region

JIP:

JNK interacting protein

JNK:

C-Jun N-terminal Kinase

MAP3K:

Mitogen-Activated Kinase kinase kinase

MAP2K:

Mitogen-Activated Protein Kinase kinase

MAPK:

Mitogen-Activated Protein Kinase

MEF:

Mouse embryonic fibroblast

MKP:

Mitogen-Activated Kinase phosphatases

MoRF:

Molecular recognition feature

NFATC3:

Nuclear factor of activated T-cells, cytoplasmic 3

NLR:

NOD-like receptor

NOD:

Nucleotide-binding oligomerization domain

PD:

Parkinson’s disease

PDB:

Protein data bank

PONDR:

Predictor of natural disordered regions

PPID:

Predicted percentage of intrinsic disorder

PTB:

Phosphotyrosine binding domain

PTM:

Posttranslational modification

RLR:

RIG-I like receptor

ROS:

Reactive oxygen species

SAPK:

Stress activated protein kinase

SLiM:

Short linear motif

TLR:

Toll-like receptor

TF:

Transcription factor

TNF-R:

Tumor necrosis factor receptor

TRAF:

Tumor necrosis factor receptor (TNF-R) associated factor

Txn:

Thioredoxin

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Funding

RG is grateful for the IYBA Award (Grant Number: BT/11/IYBA/2018/06) from the Department of Biotechnology (DBT), India; MHRD-SPARC (SPARC/2018–2019/P37/SL), Science and Engineering Research Board (SERB), India (Grant number: CRG/2019/005603), and Indian Council of Medical Research (Grant numbers: 58/6/2020/PHA/BMS, 52/04/2020/BIO/BMS). Department of Biotechnology, Ministry of Science and Technology (Grant number: BT/PR16871/NER/95/329/2015).

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  1. School of Basic Sciences, Indian Institute of Technology Mandi, VPO Kamand, Mandi, Himachal Pradesh, 175005, India

    Bhuvaneshwari R. Gehi, Kundlik Gadhave & Rajanish Giri

  2. Molecular Biophysics Unit (MBU), Indian Institute of Science, Bengaluru, 560012, India

    Bhuvaneshwari R. Gehi

  3. Department of Molecular Medicine and Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

    Vladimir N. Uversky

  4. Laboratory of New Methods in Biology, Institute for Biological Instrumentation of the Russian Academy of Sciences, Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, Pushchino, Moscow region, 142290, Russia

    Vladimir N. Uversky

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RG and VNU: conception and design, interpretation of data, writing, and review of the manuscript, and study supervision. BRG: acquisition and interpretation of data. BRG and KG: writing and review of the manuscript.

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Gehi, B.R., Gadhave, K., Uversky, V.N. et al. Intrinsic disorder in proteins associated with oxidative stress-induced JNK signaling. Cell. Mol. Life Sci. 79, 202 (2022). https://doi.org/10.1007/s00018-022-04230-4

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