Intrinsically Disordered Proteins Link Alternative Splicing and Post-translational Modifications to Complex Cell Signaling and Regulation

Zhou, Jianhong; Zhao, Suwen; Dunker, A. Keith

doi:10.1016/j.jmb.2018.03.028

Cited by 90Protein Structure and DynamicsRNA Research and SplicingReceptor Mechanisms and Signaling

Intrinsically Disordered Proteins Link Alternative Splicing and Post-translational Modifications to Complex Cell Signaling and Regulation

Zhou, Jianhong, Zhao, Suwen, Dunker, A. Keith·2018·Journal of Molecular Biology

DOI 10.1016/j.jmb.2018.03.028

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Abstract

Intrinsically disordered proteins and regions (IDPs and IDRs) lack well-defined tertiary structures, yet carry out various important cellular functions, especially those associated with cell signaling and regulation. In eukaryotes, IDPs and IDRs contain the preferred loci for both alternative splicing (AS) and many post-translational modifications (PTMs). Furthermore, AS and/or PTMs at these loci generally alter the signaling outcomes associated with these IDPs or IDRs, where the functional cooperation of these three features is named the IDP-AS-PTM toolkit. However, the prevalence of such functional modulations remains unknown. Also, the signal-altering mechanisms by which AS, and PTMs modulate function and the extent to which AS and PTMs collaborate in their signaling modulations have not been well defined for particular protein examples. Here we focus on three important signaling and regulatory IDR-containing protein families in humans, namely, G protein-coupled receptors (GPCRs), which are transmembrane proteins; the nuclear factors of activated T cells (NFATs), which are transcription factors; and the Src family kinases (SFKs), which are signaling enzymes. The goals here are to determine how AS and PTMs individually alter the outcomes of the signaling carried out by the various IDRs and to determine whether AS and PTMs work together to bring about differential cellular responses. We also present data indicating that a wide range of other signaling IDPs or IDRs undergo both AS- and PTM-based modifications, suggesting that they, too, likely take advantage of signal outcome modulations that result from collaboration between these two events. Hence, we propose that the widespread cooperation of IDPs, AS and/or PTMs provides an IDP-AS-PTM toolkit and substantially contributes to the vast complexity of eukaryotic cell signaling systems.

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The combined use of intrinsic disorder, alternative splicing and PTM widely enables the context-dependent orchestration of signaling in developmental biology and other complex processes.
“The combined use of intrinsic disorder, alternative splicing and PTM widely enables the context-dependent orchestration of signaling in developmental biology and other complex processes [38, 39].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [39]
The signaling functions carried out by GPCRs, NFATs, and SFKs are all modulated by the collaboration of PTMs and alternative splicing that map to the same IDRs.
“Indeed, the signaling functions carried out by G protein-coupled receptors (GPCRs), which are transmembrane proteins; the nuclear factors of activated T cells (NFATs), which are transcription factors; and the Src family kinases (SFKs), which are signaling enzymes, are all modulated by the collaboration of PTMs and alternative splicing that map to the same IDRs [39].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [39]
PTEN appears to take advantage of the IDP-AS-PTM Toolkit.
“Again, this protein appears to take advantage of the previously described IDP-AS-PTM Toolkit [39].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [39]
Alternative splicing and PTMs localized in intrinsically disordered regions direct differential CXCR4 signaling.
“Alternative splicing and PTMs, localized in intrinsically disordered regions, direct differential CXCR4 signaling.”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [39]

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The molecular basis for cellular function of intrinsically disordered protein regions
Holehouse, A. S., & Kragelund, B. B. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-023-00673-0 · Cited by 717 · see citing works
“Currently understudied is also the role of isoforms and proteoforms, two ways of regulating protein function for which IDRs are statistically enriched 84,370–373 .”
Cross-Linking Mass Spectrometry for Investigating Protein Conformations and Protein–Protein Interactions─A Method for All Seasons
Piersimoni, L., Kastritis, P. L., Arlt, C., & Sinz, A. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.1c00786 · Cited by 307 · see citing works
High-throughput total RNA sequencing in single cells using VASA-seq
Salmén, F., Jonghe, J. D., Kamiński, T. S., Alemany, A., Parada, G. E., Verity-Legg, J., Yanagida, A., Kohler, T. N., Battich, N., van den Brekel, F., et al. (2022) · Nature Biotechnology · doi:10.1038/s41587-022-01361-8 · Cited by 233 · see citing works
“6h,i), which predominantly contain post-translational modification and protein–protein interaction sites 50 .”
Intrinsically disordered proteins play diverse roles in cell signaling
Bondos, S. E., Dunker, A. K., & Uversky, V. N. (2022) · Cell Communication and Signaling · doi:10.1186/s12964-022-00821-7 · Cited by 222 · see citing works
“tissue or cell specific) regulation as discussed previously and above for GPCRs, N-FATs, and Sarc Family kinases [39].”
BackgroundMethodInfluentialSelf-citation
Intrinsically disordered proteins and structured proteins with intrinsically disordered regions have different functional roles in the cell
Deiana, A., Forcelloni, S., Porrello, A., & Giansanti, A. (2019) · PLoS ONE · doi:10.1371/journal.pone.0217889 · Cited by 137 · see citing works
New Binding Sites, New Opportunities for GPCR Drug Discovery
Chan, H. C. S., Li, Y., Dahoun, T., Vogel, H., & Yuan, S. (2019) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2018.11.011 · Cited by 139 · see citing works
Combinatorial expression of GPCR isoforms affects signalling and drug responses
Martí-Solano, M., Crilly, S. E., Malinverni, D., Munk, C., Harris, M., Pearce, A., Quon, T., Mackenzie, A. E., Wang, X., Peng, J., et al. (2020) · Nature · doi:10.1038/s41586-020-2888-2 · Cited by 135 · see citing works
Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding
Yang, J., Gao, M., Xiong, J., Su, Z., & Huang, Y. (2019) · Protein Science · doi:10.1002/pro.3718 · Cited by 85 · see citing works
“ments containing different functional or signaling elements allows for rewiring the cellular signaling pathways.(19,26,203) YANG ET AL.”
Background
Structural perspective of class B1 GPCR signaling
Cong, Z., Liang, Y.-L., Zhou, Q., Darbalaei, S., Zhao, F., Feng, W., Zhao, L., Xu, H. E., Yang, D., & Wang, M. (2022) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2022.01.002 · Cited by 80 · see citing works
Splice-Junction-Based Mapping of Alternative Isoforms in the Human Proteome
Lau, E., Han, Y., Williams, D. R., Thomas, C. T., Shrestha, R., Wu, J. C., & Lam, M. P. Y. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.11.026 · Cited by 67 · see citing works
Intrinsically disordered proteins and proteins with intrinsically disordered regions in neurodegenerative diseases
Coskuner‐Weber, O., Mirzanli, O., & Uversky, V. N. (2022) · Biophysical Reviews · doi:10.1007/s12551-022-00968-0 · Cited by 69 · see citing works
Intrinsically Disordered Proteins: Structure, Function and Therapeutics
Chen, J., & Kriwacki, R. W. (2018) · Journal of Molecular Biology · doi:10.1016/j.jmb.2018.06.012 · Cited by 58 · see citing works
“This Special Issue contains five review articles [1], [2], [3], [4], [5] and 14 original research articles [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19] that address some of the latest advances, central mechanistic questions, and emerging frontiers related to IDPs in biology and diseas…”
Background
Intrinsic disorder is an essential characteristic of components in the conserved circadian circuit
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Authors: Zhou, J., Zhao, S., & Dunker, A. K.
Affiliations: ShanghaiTech University (CN)
Indiana University Indianapolis (US)
Corresponding author: Zhao, Suwen
Dunker, A. Keith
ORCID: Zhao, Suwen
Dunker, A. Keith
Venue: Journal of Molecular Biology
Publisher: Elsevier BV
Published: 2018-08
Volume: 430
Issue: 16
Pages: 2342-2359
ISSN: 0022-2836 (ISSN-L)
DOI: 10.1016/j.jmb.2018.03.028
OpenAlex: W2796408051
Cited by: 90
References: 159
Citations by year: 2026: 3 · 2025: 6 · 2024: 12 · 2023: 13 · 2022: 15 · 2021: 8 · 2020: 10 · 2019: 19 · 2018: 4
FWCI: 3.65
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Journal of Molecular Biology (publishedVersion)
PubMed (publishedVersion)
IUScholarWorks (Indiana University) (submittedVersion)
Author eBooks
Funders: ShanghaiTech University
Science and Technology Commission of Shanghai Municipality (16ZR1448500)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords: intrinsically disordered proteins, intrinsically disordered regions, alternative splicing, post-translational modification, signal transduction, G protein-coupled receptors, NFAT transcription factors, Src family kinases, protein structure-function relationship
MeSH terms: Biochemical Phenomena, Humans, Protein Binding, Protein Conformation, Protein Processing, Post-Translational, Signal Transduction, Alternative Splicing, src-Family Kinases, Receptors, G-Protein-Coupled, NFATC Transcription Factors, Intrinsically Disordered Proteins

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Intrinsically Disordered Proteins Link Alternative Splicing and Post-translational Modifications to Complex Cell Signaling and Regulation

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