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Chaotic aging: intrinsically disordered proteins in aging-related processes

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A Correction to this article was published on 13 January 2024

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Abstract

The development of aging is associated with the disruption of key cellular processes manifested as well-established hallmarks of aging. Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) have no stable tertiary structure that provide them a power to be configurable hubs in signaling cascades and regulate many processes, potentially including those related to aging. There is a need to clarify the roles of IDPs/IDRs in aging. The dataset of 1702 aging-related proteins was collected from established aging databases and experimental studies. There is a noticeable presence of IDPs/IDRs, accounting for about 36% of the aging-related dataset, which is however less than the disorder content of the whole human proteome (about 40%). A Gene Ontology analysis of the used here aging proteome reveals an abundance of IDPs/IDRs in one-third of aging-associated processes, especially in genome regulation. Signaling pathways associated with aging also contain IDPs/IDRs on different hierarchical levels, revealing the importance of "structure-function continuum" in aging. Protein–protein interaction network analysis showed that IDPs present in different clusters associated with different aging hallmarks. Protein cluster with IDPs enrichment has simultaneously high liquid–liquid phase separation (LLPS) probability, “nuclear” localization and DNA-associated functions, related to aging hallmarks: genomic instability, telomere attrition, epigenetic alterations, and stem cells exhaustion. Intrinsic disorder, LLPS, and aggregation propensity should be considered as features that could be markers of pathogenic proteins. Overall, our analyses indicate that IDPs/IDRs play significant roles in aging-associated processes, particularly in the regulation of DNA functioning. IDP aggregation, which can lead to loss of function and toxicity, could be critically harmful to the cell. A structure-based analysis of aging and the identification of proteins that are particularly susceptible to disturbances can enhance our understanding of the molecular mechanisms of aging and open up new avenues for slowing it down.

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Data availability

The authors confirm that the data supporting the findings of this study are available within the article and also present as electronic supplementary materials. Additional data will be available on reasonable request.

Change history

Abbreviations

IDP:

Intrinsically disordered protein

IDR:

Intrinsically disordered region

PONDR:

Predictor of natural disordered regions

PONDR-FIT, VLXT, VL3, VSL2, IUPred2A:

Predictors of protein disorder (existence of the disordered residues in the protein) from PONDR family

MDS:

Mean disorder score—average of PONDR scores of each residue for whole protein

PPIDR:

Predicted percentage of intrinsically disordered residues (with propensity to be disordered higher than 0.5)

CDF:

Cumulative distribution function

CH:

Charge–hydropathy

MoRF:

Molecular recognition features (protein–partner interaction sites that acquire structure upon binding to partners)

LLPS:

Liquid–liquid phase separation

FuzDrop, PSPredictor, PScore:

Predictors of the LLPS propensity

PPI:

Protein–protein interaction

BP:

Biological process

AggreScan, PASTA2:

Predictors of the aggregation propensity

IIS:

Insulin and insulin-like signaling

DR:

Dietary restriction

TERT:

Telomerase catalytic unit

nFoE:

Normalized fold enrichment

ML:

Machine learning

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Acknowledgements

NI acknowledges the Ministry of Science and Higher Education of the Russian Federation (Agreement # 075-03-2023-106, Project FSMG-2020-0003, in the part of analysis of protein-protein interactions. The research was also supported by the Ministry of Science and Higher Education of the Russian Federation (Agreement # 075-01593-23-04, Project 720000F.99.1.BN62AA40000) in the part of aggregation evaluation. The part of this work (LLPS analysis) was funded by Russian Science Foundation, Grant number 21-75-10166 (A.V.F.).

Funding

This work was supported in part by the Ministry of Science and Higher Education of the Russian Federation (Agreement # 075-03-2023-106, Project FSMG-2020-0003; and Agreement # 075-01593-23-04, Project 720000F.99.1.BN62AA40000). The part of this work was funded by Russian Science Foundation (Grant number 21-75-10166).

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  1. Vladimir D. Manyilov and Nikolay S. Ilyinsky contributed equally.

Authors and Affiliations

  1. Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Institutskiy Pereulok, 9, Dolgoprudny, 141700, Russia

    Vladimir D. Manyilov, Nikolay S. Ilyinsky, Semen V. Nesterov, Baraa M. G. A. Saqr, Egor V. Zinovev, Simon S. Matrenok, Valentin Ivanovich & Vladimir N. Uversky

  2. Institute of Cytology, Russian Academy of Sciences, Saint Petersburg, 194064, Russia

    Semen V. Nesterov, Alexander V. Fonin, Irina M. Kuznetsova & Konstantin K. Turoverov

  3. Department of Chemistry, University of South Florida, Tampa, FL, USA

    Guy W. Dayhoff II

  4. Department of Molecular Medicine and USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., MDC07, Tampa, FL, 33612, USA

    Vladimir N. Uversky

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Contributions

VDM and NSI contributed equally to this work. NSI, VI, and VNU conceived and designed study. VDM, NSI, SVN, BMGAS, GWD, EVZ, SSM, AVF, IMK, KKT, and VNU conducted research, analyzed data, and collected and analyzed literature data. VDM, NSI, SVN, BMGAS, GWD, EVZ, and SSM designed illustrations. VDM, NSI, SVN, BMGAS, GWD, EVZ, SSM, AVF, IMK, KKT, VI, and VNU wrote the manuscript. All the authors have read and agreed to the published version of the manuscript.

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Correspondence to Nikolay S. Ilyinsky or Vladimir N. Uversky.

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Manyilov, V.D., Ilyinsky, N.S., Nesterov, S.V. et al. Chaotic aging: intrinsically disordered proteins in aging-related processes. Cell. Mol. Life Sci. 80, 269 (2023). https://doi.org/10.1007/s00018-023-04897-3

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