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Cited by 222Protein Structure and DynamicsReceptor Mechanisms and SignalingProtein Kinase Regulation and GTPase Signaling

Intrinsically disordered proteins play diverse roles in cell signaling

Open access
Bondos, Sarah E., Dunker, A. Keith, Uversky, Vladimir N.·2022·Cell Communication and Signaling
DOI 10.1186/s12964-022-00821-7PMC PMC8851865
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Abstract

Signaling pathways allow cells to detect and respond to a wide variety of chemical (e.g. Ca 2+ or chemokine proteins) and physical stimuli (e.g., sheer stress, light). Together, these pathways form an extensive communication network that regulates basic cell activities and coordinates the function of multiple cells or tissues. The process of cell signaling imposes many demands on the proteins that comprise these pathways, including the abilities to form active and inactive states, and to engage in multiple protein interactions. Furthermore, successful signaling often requires amplifying the signal, regulating or tuning the response to the signal, combining information sourced from multiple pathways, all while ensuring fidelity of the process. This sensitivity, adaptability, and tunability are possible, in part, due to the inclusion of intrinsically disordered regions in many proteins involved in cell signaling. The goal of this collection is to highlight the many roles of intrinsic disorder in cell signaling. Following an overview of resources that can be used to study intrinsically disordered proteins, this review highlights the critical role of intrinsically disordered proteins for signaling in widely diverse organisms (animals, plants, bacteria, fungi), in every category of cell signaling pathway (autocrine, juxtacrine, intracrine, paracrine, and endocrine) and at each stage (ligand, receptor, transducer, effector, terminator) in the cell signaling process. Thus, a cell signaling pathway cannot be fully described without understanding how intrinsically disordered protein regions contribute to its function. The ubiquitous presence of intrinsic disorder in different stages of diverse cell signaling pathways suggest that more mechanisms by which disorder modulates intra- and inter-cell signals remain to be discovered. Graphical abstract:

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Written from the paper’s full text.

TL;DR

This review argues that intrinsically disordered proteins/regions are pervasive and functionally critical across cell signaling, from ligands and receptors to transducers, effectors, and terminators, in all kingdoms and signaling categories. It synthesizes examples and mechanisms—binding-induced folding, fuzzy complexes, PTM/alternative-splicing integration, scaffolding, and allostery—showing that signaling pathways cannot be fully described without considering intrinsic disorder.

Key findings

  • IDPs/IDRs are present in signaling proteins across animals, plants, bacteria, and fungi, and in every signaling category (autocrine, juxtacrine, intracrine, paracrine, endocrine) and at each stage (ligand, receptor, transducer, effector, terminator).
  • Disorder enables key signaling properties: binding-induced folding decouples affinity from specificity; fuzzy complexes preserve disorder in bound states; low energetic barriers support reversible sensing; IDRs facilitate allosteric regulation, PTM/alternative-splicing integration (the IDP-AS-PTM toolkit), and scaffold-mediated amplification.
  • In the Wnt pathway analysis of 117 proteins, no proteins were very structured and only two were mostly disordered; the remaining 115 were moderately or highly disordered. Other examples include a 111-amino-acid intrinsically disordered region in the Notch intracellular domain, a 148-amino-acid disordered connexin C-terminal domain, an 852-residue mostly disordered axin scaffold, a 2,843-residue massively disordered APC protein, and Gab2 (74 kDa) with a ~550-amino-acid disordered region in which only two ~20-amino-acid regions bind Grb2.
  • Proteome predictions indicate ~15–30% of encoded residues are disordered in archaeal/eubacterial proteomes and ~30–50% in eukaryotic proteomes; top three disorder predictors achieved balanced accuracies of 76–80% on 646 proteins; >90% of transcription factors contain IDRs or are entirely disordered; and 15% of all disordered proteins bind lipid.

Methods

  • Narrative review, not primary research. The stated aims are to summarize best practices for identifying intrinsically disordered regions, highlight diverse cell signaling pathways that employ disordered proteins, and identify known molecular mechanisms implemented by these proteins and regions.
  • Evidence base includes literature examples across kingdoms and pathway categories, computational disorder predictions and tools (e.g., PONDR, IUPred, MoRF/ANCHOR predictors), and cited experimental studies; it includes a summary table of ID-enabled mechanisms.
  • No systematic search strategy, inclusion criteria, or meta-analysis is described in the text.

Limitations

  • The paper does not state a formal limitations section.
  • Evident from the text: it is a narrative review with illustrative examples rather than a systematic or exhaustive survey; some analyses are described as “work in progress” (e.g., protein interaction domains binding DBRs in IDRs), and some epigenetic implications are stated as unknown to the authors.
  • Evident: many mechanistic claims rely on computational predictions and cited secondary literature, and the review notes that more mechanisms by which disorder modulates signaling remain to be discovered.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1186/s12964-022-00821-7

Cites

331 of 331 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 192 cited sources checked · 0 supported · 0 flagged

  • Findingreasoning

    The remaining 115 Wnt pathway proteins are either moderately disordered or highly disordered.

    “The remaining 115 proteins are either moderately disordered or highly disordered”
    Quote in the paperNot a substantial claim
  • Interpretationnone given

    The sensitivity, adaptability, and tunability of cell signaling are possible, in part, due to the inclusion of intrinsically disordered regions in many proteins involved in cell signaling.

    “This sensitivity, adaptability, and tunability are possible, in part, due to the inclusion of intrinsically disordered regions in many proteins involved in cell signaling.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Some IDPs/IDRs may remain unfolded and dynamic even in the bound state, creating fuzzy complexes.

    “Some IDPs/IDRs may remain unfolded and dynamic even in the bound state [19–23], creating fuzzy complexes (Fig. 1) [24, 25].”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [19] Borgia A, Borgia MB, Bugge K, Kissling VM, Heidarsson PO, Fernandes CB, et al. Extreme disorder in an ultrahigh-affinity protein complex. Nature. 2018;55:61–6. source

      Not checked in the free run.

    • cites [20] Borg M, Mittag T, Pawson T, Tyers M, Forman-Kay JD, Chan HS. Polyelectrostatic interactions of disordered ligands suggest a physical basis for ultrasensitivity. Proc Natl Acad Sci USA. 2007;104:9650–5. source

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    • cites [21] Permyakov SE, Millett IS, Doniach S, Perkyakov EA, Uversky VN. Natively unfolded C-terminal domain of caldesmon remains substantially unstructured after the effective binding to calmodulin. Proteins. 2003;53:855–62. source

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    • cites [22] Sigalov AB, Zhuravleva A, Orekhov VY. Binding of intrinsically disordered proteins is not necessarily accompanied by a structural transition to a folded form. Biochimie. 2007;89:419–21. source

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    • cites [23] Sigalov AB. Protein intrinsic disorder and oligomericity in cell signaling. Mol Biosyst. 2010;6:451–61. source

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    • cites [24] Fuxreiter M, Simon I, Bondos S. Dynamic protein-DNA recognition: beyond what can be seen. Trends Biochem Sci. 2011;36:415–23. source

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    • cites [25] Fuxreiter M, Tompa P. Fuzzy complexes: a more stochastic view of protein function. Adv Exp Med Biol. 2012;725:1–14. source

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  • Premisecitation

    Many IDPs/IDRs are capable of at least partial ordering upon interaction with specific partners.

    “Many IDPs/IDRs are capable of at least partial ordering upon interaction with specific partners [7–18].”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [7] Wright PE, Dyson HJ. Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm. J Mol Biol. 1999;293:321–31. source

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    • cites [8] Dunker AK, Obradović Z. The protein trinity - linking function and disorder. Nat Biotechnol. 2001;19:805–6. source

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    • cites [9] Dunker AK, Brown CJ, Lawson JD, Iakoucheva LM, Obradović Z. Intrinsic disorder and protein function. Biochemistry. 2002;41:6573–82. source

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    • cites [10] Dunker AK, Cortese MS, Romero P, Iakoucheva LM, Uversky VN. Flexible nets: the roles of intrinsic disorder in protein interaction networks. FEBS J. 2005;272:5129–48. source

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    • cites [11] Daughdrill GW, Pielak GJ, Uversky VN, Cortese MS, Dunker AK. Natively disordered proteins. In: Buchner J, Kiefhaber T, editors. Handbook of protein folding. Weinheim: Wiley, Verlag GmbH & Co KGaA; 2005. p. 271–353.

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    • cites [12] Dyson HJ, Wright PE. Coupling of folding and binding for unstructured proteins. Curr Opin Struct Biol. 2002;12:54–60. source

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    • cites [13] Wright DHJPE. Intrinsically unstructured proteins and their functions. Nat Rev Mol Cell Biol. 2005;6:197–208. source

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    • cites [14] Iakoucheva LM, Brown CJ, Lawson JD, Obradović Z, Dunker AK. Intrinsic disorder in cell-signaling and cancer-associated proteins. J Mol Biol. 2002;323:573–84. source

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    • cites [15] Plaxco KW, Gross M. Cell biology. The importance of being unfolded. Nature. 1997;386:657–9. source

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    • cites [16] Pontius BW. Close encounters: why unstructured, polymeric domains can increase rates of specific macromolecular association. Trends Biochem Sci. 1993;18:181–6. source

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  • Interpretationreasoning

    The conflicting needs of cell signaling (e.g., specificity vs. reversibility) have been resolved to a large extent by including intrinsically disordered proteins in cell signaling pathways through biological evolution.

    “These conflicting needs have been resolved to a large extent by including intrinsically disordered proteins in cell signaling pathways through biological evolution.”
    Quote in the paperSubstantial claim
  • May combine two claims. 63
  • Classified as probably not a substantial claim. 11

  • May combine two claims.

    Findingown data

    The N-terminal domain and a hinge region of human glucocorticoid receptor are mostly disordered.

    “Clearly, the N-terminal domain and a hinge region are mostly disordered”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [179] Obradovic Z, Peng K, Vucetic S, Radivojac P, Dunker AK. Exploiting heterogeneous sequence properties improves prediction of protein disorder. Protein. 2005;61:176–82. source

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    • cites [180] Obradovic Z, Peng K, Vucetic S, Radivojac P, Brown CJ, Dunker AK. Predicting intrinsic disorder from amino acid sequence. Protein. 2003;53:566–72. source

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    • cites [181] Xue B, Dunbrack RL, Williams RW, Dunker AK, Uversky VN. PONDR-FIT: a meta-predictor of intrinsically disordered amino acids. Biochim Biophys Acta. 2010;1804:996–1010. source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Analysis of 117 proteins involved in Wnt signaling based on disorder score and percent of disordered residues showed that no Wnt pathway proteins are very structured and only two proteins can be considered mostly disordered.

    “It is noteworthy that no Wnt pathway proteins are very structured (dark blue) and only two proteins can be considered”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    More than 30 protein interaction domains have been shown by published experiments and/or by prediction to bind to DBRs in IDRs, with none so far binding to structured domains.

    “So far more than 30 of these protein interaction domains have been shown by published experiments and/or by prediction to bind to DBRs in IDRs, with none so far binding to structured domains (work in progress).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Binding-induced folding decouples binding affinity from specificity, enabling cell signaling to be reversible.

    “Thus binding-induced folding decouples binding affinity from specificity, enabling cell signaling to be reversible.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Histone H1 and its nuclear chaperone prothymosin-α form a picomolar affinity complex, but preserve completely their structural disorder, long-range flexibility, and highly dynamic character.

    “An extreme example of this behavior is provided by two highly disordered human proteins, histone H1 and its nuclear chaperone prothymosin-α, which form a picomolar affinity complex, but in which they preserve completely their structural disorder, their long-range flexibility, and their highly dynamic character [19].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Borgia A, Borgia MB, Bugge K, Kissling VM, Heidarsson PO, Fernandes CB, et al. Extreme disorder in an ultrahigh-affinity protein complex. Nature. 2018;55:61–6. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PTEN contains an N-terminal PI(4,5)P2 binding site, a structured catalytic domain, and an intrinsically disordered auto-inhibitory C-terminal tail culminating in a PDZ binding domain.

    “The PTEN protein contains an N-terminal PI(4,5)P2 binding site, and a structured catalytic domain followed by an intrinsically disordered auto-inhibitory C-terminal tail which culminates in a PDZ binding domain [188, 189].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [188] Lesli NR, Batty IH, Maccario H, Davidson L, Downes CP. Understanding PTEN regulation: PIP2, polarity and protein stability. Oncogene. 2008;27:5464–76. source

      Not checked in the free run.

    • cites [189] Odriozola L, Singh G, Hoang T, Chang AM. Regulation of PTEN activity by its carboxyl-terminal autoinhibitory domain. J Biol Chem. 2007;282:23306–15. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The concentration of both PTMs and segments encoded by alternative splicing within IDRs suggest these two sequence modifications may be co-localized, providing an opportunity to integrate two different regulatory inputs.

    “The concentration of both PTMs and segments encoded by alternative splicing within IDRs suggest these two sequence modifications may be co-localized, providing an opportunity to integrate two different regulatory inputs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Phosphorylation and many but not all other PTMs show a strong preference to be localized in IDRs.

    “Likewise, phosphorylation [41] and many but not all other PTMs [42] show a strong preference to be localized in IDRs, likely because flexibility enhances the ability of a motif, destined for PTM addition, to enter and bind to the active site of the corresponding enzyme.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [41] Iakoucheva LM, Radivojac P, Brown CJ, O’Connor TR, Sikes JG, Obradovic Z, Dunker AK. The importance of intrinsic disorder for protein phosphorylation. Nucleic Acids Res. 2004;32:1037–49. source

      Not checked in the free run.

    • cites [42] Gao J, Xu D. Correlation between posttranslational modification and intrinsic disorder in protein. In: Pacific symposium on Biocomputing;2012. p. 94–103. source

      Not checked in the free run.

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    Premisecitation

    PTEN is a powerful tumor suppressor and a prognostic marker that predicts response in many human cancers.

    “Consequently, PTEN is not only a powerful tumor suppressor, but also a prognostic marker that predicts response in many human cancers [187].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [187] Mingo J, Luna S, Gaafar A, Nunes-Xavier E, Torices L, Mosteiro L. Precise definition of PTEN C-terminal epitopes and its implications in clinical oncology. Precision Oncol. 2019;3:11. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Because some signaling IDPs/IDRs lack stable secondary structure, the energetic barriers between the bound and free states are low, allowing disordered regions to act as reversible, extremely sensitive sensors.

    “Because some signaling IDPs/IDRs lack stable (secondary) structure, the energetic barriers between the bound and free states are low, allowing disordered regions to act as reversible, extremely sensitive sensors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Disordered proteins provide many avenues for integrating multiple signaling pathways, including providing a scaffold that binds proteins from multiple pathways, regulating multiple disordered substrates through PTMs, and varying pathway components through alternative mRNA splicing.

    “Finally, disordered proteins provide many avenues for integrating multiple signaling pathways [27], including providing a scaffold that binds proteins from multiple pathways [34], regulating multiple disordered substrates through PTMs, and varying pathway components through alternative mRNA splicing [35–37].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [27] Kreiger JM, Fusco G, Lewitzky M, Simister PC, Marchant J, Camilloni C, et al. Conformational recognition of an intrinsically disordered protein. Biophys J. 2014;106:1771–9. source

      Not checked in the free run.

    • cites [34] Martin-Yken H, Francois JM, Zerbib D. Knr4: a disordered hub protein at the heart of fungal cell wall signalling. Cell Microbiol. 2016;18:1217–27. source

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    • cites [35] Gough J, Dunker AK. Sequences and topology: disorder, modularity, and post/pre-translation modifications. Curr Opin Struct Biol. 2013;23:417–9. source

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    • cites [36] Kawamura H, Li X, Harper SJ, Bates DO, Claesson-Welsh L. Vascular endothelial growth factor (VEGF)-A165b is a weak in vitro agonist for VEGF receptor-2 due to lack of coreceptor binding and deficient regulation of kinase activity. Cancer Res. 2008;68:4683–92. source

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    • cites [37] Li J, White JT, Saavedra H, Wrabl JO, Motlagh HN, Liu K, Sower J, et al. Genetically tunable frustration controls allostery in an intrinsically disordered transcription factor. eLife. 2017;6:e30688. source

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  • May combine two claims.

    Premisecitation

    These differences can carry over to following generations, indicating that these multiple PTMs provide the basis for an epigenetic mechanism.

    “These differences can carry over to following generations, indicating that these multiple PTMs provide the basis for an epigenetic mechanism.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Strahl BD, Allis CD. The language of covalent histone modifications. Nature. 2000;403:41–5. source

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    Premisecitation

    Histone tails may be accessible or may adhere to the nucleosome and be inaccessible for protein interactions, demonstrating that the context provided by the nucleosome is also a key contributor.

    “Finally, histone tails may be accessible or may adhere to the nucleosome and be inaccessible for protein interactions, demonstrating that the context provided by the nucleosome is also a key contributor [53].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Morrison EA, Bowerman S, Sylvers KL, Wereszczynski J, Musselman CA. The conformation of the histone H3 tail inhibits association of the BPTG PHD finger with the nucleosome. eLife. 2018;7:e31481. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Ligand or protein interactions shift the conformational ensemble of the IDP/IDR, linking protein function to binding.

    “Whether or not stable structure results from the interaction, ligand or protein interactions shift the conformational ensemble of the IDP/IDR, linking protein function to binding.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Phosphorylation of most serine/threonine residues in the PTEN tail forces PTEN into a closed, more stable, inactive conformation in which membrane association, PDZ binding, ubiquitination, and degradation are suppressed.

    “Phosphorylation of most of these amino acids forces PTEN into a closed, more stable, inactive conformation, in which membrane association, PDZ binding, ubiquitination, and degradation are all suppressed [188, 190].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [188] Lesli NR, Batty IH, Maccario H, Davidson L, Downes CP. Understanding PTEN regulation: PIP2, polarity and protein stability. Oncogene. 2008;27:5464–76. source

      Not checked in the free run.

    • cites [190] Rahdar M, Inoue T, Zhang J, Vazquez F, Devreotes PN. A phosphorylation-dependent intramolecular interactions regulates the membrane association and activity of the tumor suppressor PTEN. Proc Natl Acad Sci USA. 2009;106:480–5. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The supplemental data in Zhou et al., 2018 show that all of these proteins undergo alternative splicing, suggesting the possibility that alternative splicing could be a previously unsuspected regulator of the epigenetic effects resulting from the histone code.

    “Furthermore, the supplemental data in Zhou et al., 2018 show that all of these proteins undergo alternative splicing, suggesting the possibility that alternative splicing could be a previously unsuspected regulator of the epigenetic effects resulting from the histone code [39].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Zhou J, Zhao S, Dunker AK. Intrinsically disordered proteins link alternative splicing and post-translational modifications to complex cell signaling and regulation. J Mol Biol. 2018;430:2342–59. source

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  • May combine two claims.

    Premisecitation

    Inactive PTEN exists in a cytoplasmic pool and lacks substrate access.

    “Inactive PTEN exists in a cytoplasmic pool and lacks substrate access [188].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [188] Lesli NR, Batty IH, Maccario H, Davidson L, Downes CP. Understanding PTEN regulation: PIP2, polarity and protein stability. Oncogene. 2008;27:5464–76. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    IDRs are an important feature of both the PTM code and the epigenetic effects observed for the histone code.

    “Thus, IDRs are an important feature of both the PTM code and the epigenetic effects observed for the histone code.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Osteopontin is a multifunctional cytokine with key roles in inflammation, cell viability, and tissue repair, and functions as a bone matrix protein mediating osteoclast adhesion.

    “Osteopontin is a multifunctional cytokine with key roles in inflammation, cell viability, and tissue repair, which also functions as a bone matrix protein that mediates osteoclast adhesion [196, 197].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [196] Icer MA, Gezmen-Karadag M. The multiple functions and mechanisms of osteopontin. Clin Biochem. 2018;59:17–24. source

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    • cites [197] O’Regan A, Berman JS. Osteopontin: a key cytokine in cell-mediated and granulomatous inflammation. Int J Exp Pathol. 2000;81:373–90. source

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  • May combine two claims.

    Premisecitation

    Interactions with other proteins via the PDZ binding domain or other regions enhance PTEN stability and diversify its function.

    “Interactions with other proteins via the PDZ binding domain or other regions of the protein both enhances PTEN stability and diversifies its function [188, 192].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [188] Lesli NR, Batty IH, Maccario H, Davidson L, Downes CP. Understanding PTEN regulation: PIP2, polarity and protein stability. Oncogene. 2008;27:5464–76. source

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    • cites [192] Malaney P, Uversky VN, Davé V. Identification of intrinsically disordered region in PTEN and delineation of its function via a network approach. Methods. 2015;77–78:69–74. source

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    Premisecitation

    The ability of IDPs/IDRs to persist in extreme conditions allows them to reliably sense extreme conditions and instigate responsive signaling pathways.

    “This trait allows IDPs to reliably sense extreme conditions and instigate responsive signaling pathways [26].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Launay H, Receveur-Brechot V, Carriere F, Gontero B. Ochestration of algal metabolism by protein disorder. Arch Biochem Biophys. 2019;672:108070. source

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  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Signaling pathways activated by proteins often are regulated by IDPs/IDRs in multiple steps of the pathway.

    “Signaling pathways activated by proteins often are regulated by IDPs/IDRs in multiple steps of the pathway.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    PTEN and PTEN-L exhibit different substrate specificities and mechanisms of membrane binding.

    “Thus, it is not surprising that PTEN and PTEN-L exhibit different substrate specificities and mechanisms of membrane binding [195].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [195] Masson GR, Perisic O, Burke JE, Williams RL. The intrinsically disordered tails of PTEN and PTEN-L have distinct roles in regulating substrate specificity and membrane activity. Biochem J. 2016;473:135–44. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In humans, there are more than 850 different GPCRs that are capable of being recognized and activated by more than one thousand natural and artificial extracellular ligands.

    “The complexity of this machinery is determined by the multitude of the members of the GPCR family (in humans, there are more than 850 different GPCRs [202–205]) that are capable of being recognized and activated by more than one thousand natural and artificial extracellular ligands, ranging from photons to amines, lipids, nucleotides, organic odorants, peptides, and proteins [30, 204].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [202] Bjarnadottir TK, Gloriam DE, Hellstrand SH, Kristiansson H, Fredriksson R, Schioth HB. Comprehensive repertoire and phylogenetic analysis of the G protein-coupled receptors in human and mouse. Genomics. 2006;88:263–73. source

      Not checked in the free run.

    • cites [203] Anantharaman V, Abhiman S, de Souza RF, Aravind L. Comparative genomics uncovers novel structural and functional features of the heterotrimeric GTPase signaling system. Gene. 2011;475:63–78. source

      Not checked in the free run.

    • cites [204] Fredriksson R, Lagerstrom MC, Lundin LG, Schioth HB. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol. 2003;63:1256–72. source

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    • cites [205] Southan C, Sharman JL, Benson HE, Faccenda E, Pawson AJ, Alexander SP, et al. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. Nucl Acids Res. 2016;44:D1054–68. source

      Not checked in the free run.

    • cites [30] Flock T, Hauser AS, Lund N, Gloriam DE, Balaji S, Babu MM. Selectivity determinants of GPCR-G-protein binding. Nature. 2017;545:317–22. source

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  • May combine two claims.

    Premisecitation

    The extent of disorder, and thus the activity, of CP12 is determined by redox conditions, although CP12 remains highly mobile in both the oxidized and reduced states.

    “The extent of disorder, and thus the activity, of CP12 is determined by redox conditions, although CP12 remains highly mobile in both the oxidized and reduced states.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Launay H, Receveur-Brechot V, Carriere F, Gontero B. Ochestration of algal metabolism by protein disorder. Arch Biochem Biophys. 2019;672:108070. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cells contain about 40 regulator of G signaling (RGS) proteins capable of interaction with various Gαβγ heterotrimers or their dissociated subunits.

    “Furthermore, cells contain ~ 40 of the regulator of G signaling (RGS) proteins (which are G protein effectors, modulators, and scaffold proteins) that are capable of interaction with various Gαβγ heterotrimers or their dissociated subunits [212].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [212] Temple BR, Jones CD. Jones AM (2010) Evolution of a signaling nexus constrained by protein interfaces and conformational States. PLoS Comput Biol. 2010;6:e1000962. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In humans, there are 23 Gα, 6 Gβ, and 12 Gγ subunits that can be assembled into numerous different heterotrimers.

    “In humans, there are 23 Gα, 6 Gβ, and 12 Gγ subunits that can be assembled into numerous different heterotrimers [211].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [211] Downes GB, Gautam N. The G protein subunit gene families. Genomics. 1999;62:544–52. source

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    Premisecitation

    Multiple alternate translation and splicing start sites in the PTEN gene create many versions of the protein, most notably PTEN-L, which contains an extra 173 amino acids on the N-terminus.

    “Multiple alternate translation and splicing start sites in the PTEN gene creates many versions of the protein, most notably PTEN-L, which contains an extra 173 amino acids on the N-terminus [187, 192, 193].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [187] Mingo J, Luna S, Gaafar A, Nunes-Xavier E, Torices L, Mosteiro L. Precise definition of PTEN C-terminal epitopes and its implications in clinical oncology. Precision Oncol. 2019;3:11. source

      Not checked in the free run.

    • cites [192] Malaney P, Uversky VN, Davé V. Identification of intrinsically disordered region in PTEN and delineation of its function via a network approach. Methods. 2015;77–78:69–74. source

      Not checked in the free run.

    • cites [193] Masson GR, Williams RL. Structural mechanisms of PTEN regulation. Cold Spring Harbor Perspect Med. 2020;10:a036152. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The PTEN-L extra N-terminal region is primarily disordered and post-translationally modified.

    “This region is also primarily disordered and post-translationally modified [192].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [192] Malaney P, Uversky VN, Davé V. Identification of intrinsically disordered region in PTEN and delineation of its function via a network approach. Methods. 2015;77–78:69–74. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Addition of the extra 6 amino acids reverses the function of VEGF: VEGF165 is a potent stimulator of angiogenesis, while VEGF165b binds VEGF receptors but fails to activate them in a robust, sustained manner.

    “This addition reverses the function of VEGF: while VEGF165 is a potent stimulator of angiogenesis, VEGF165b binds VEGF receptors but fails to activate them in a robust, sustained manner.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [36] Kawamura H, Li X, Harper SJ, Bates DO, Claesson-Welsh L. Vascular endothelial growth factor (VEGF)-A165b is a weak in vitro agonist for VEGF receptor-2 due to lack of coreceptor binding and deficient regulation of kinase activity. Cancer Res. 2008;68:4683–92. source

      Not checked in the free run.

    • cites [200] Woolard J, Wang WY, Bevan HS, Qiu Y, Morbidelli L, Pritchard-Jones RO, et al. VEGF165b, an inhibitory vascular endothelial growth factor splice variant: mechanism of action in vivo effect on aniogenesis and endogenous protein expression. Cancer Res. 2004;64:7822–35. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High-resolution solution NMR spectroscopy demonstrated that the long-lived pB intermediate of PYP is characterized by a noticeable level of disorder and exists as an ensemble of multiple conformers interconverting on a millisecond time scale.

    “High-resolution solution NMR spectroscopy demonstrated that this long-lived pB intermediate is characterized by a noticeable level of disorder and exists as an ensemble of multiple conformers interconverting on a millisecond time scale [220].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [220] Rubinstenn G, Vuister GW, Mulder FAA, Düx PE, Boelens R, Hellingwerf KJ, et al. Structural and dynamic changes of photoactive yellow protein during its photocycle in solution. Nat Struct Biol. 1998;5:568–70. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In dark or oxidizing conditions, CP12 forms limited, marginally stable structure and 2 disulfide bonds which are required to bind and inactivate GAPDH and PRK.

    “In dark or oxidizing conditions, CP12 forms limited, marginally stable structure and 2 disulfide bonds which are required to bind and inactivate two enzymes that participate in the Calvin-Benson-Bassham cycle (glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and phorphoribulokinase (PRK)).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Launay H, Receveur-Brechot V, Carriere F, Gontero B. Ochestration of algal metabolism by protein disorder. Arch Biochem Biophys. 2019;672:108070. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Human GPCRs and G proteins represent dynamic conformational ensembles containing multiple IDPRs and numerous PTMs and MoRFs, and their entire mode of action is based on recognition of a signal followed by conformational change needed for recognition of another partner crucial for downstream transmission.

    “In fact, human GPCRs and G proteins represent dynamic conformational ensembles containing multiple IDPRs and numerous PTMs and MoRFs, and the entire mode of action of these proteins is based on the recognition of a signal followed by conformational change needed for recognition of another partner that is crucial for the downstream transmission of the signal [213].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [213] Fonin AV, Darling AL, Kuznetsova IM, Tuoverov KK, Uversky VN. Multi-functionality of proteins involved in GPCR and G protein signaling: making sense of structure-function continuum with intrinsic disorder-based proteoforms. Cell Mol Life Sci. 2019;76:4461–92. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Photoexcitation of UVR8 triggers dimer dissociation and enables the extended C-terminal tail to bind COP1, which regulates light signaling in plants, and propagates the signal.

    “Photoexcitation of UVR8 triggers dimer dissociation and enables the extended C-terminal tail to bind COP1, which regulates light signaling in plants, and propagates the signal [162].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] Camacho IS, Theisen A, Johannissen LO, Diaz-Raos LA, Christie JM, Jenkins GI, et al. Native mass spectrometry reveals the conformational diversity of the UVR8 photoreceptor. Proc Natl Acad Sci USA. 2019;116:1116–25. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In light/reducing conditions, the disulfide bonds break and the CP12-GAPDH-PRK ternary complex dissociates, re-activating the enzymes and thus carbon fixation.

    “In light/reducing conditions, the disulfides bonds break and the CP12-GAPDH-PRK ternary complex dissociates, re-activating the enzymes and thus carbon fixation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Launay H, Receveur-Brechot V, Carriere F, Gontero B. Ochestration of algal metabolism by protein disorder. Arch Biochem Biophys. 2019;672:108070. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Most intrinsically disordered proteins with well-studied roles in signaling operate in endocrine signaling pathways.

    “Most of the intrinsically disordered proteins with well-studied roles in signaling operate in endocrine signaling pathways.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Phosphorylation of the C-terminal domain of Connexin 43 inhibits channel function, whereas phosphorylation of Connexin 32 stimulates channel function.

    “Phosphorylation of the C-terminal domain of Connexin 43 inhibits channel function, whereas phosphorylation of Connexin 32 stimulates channel function [254].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [254] Trease AJ, Li H, Spagnol G, Zheng L, Stauch KL, Sorgen PL. Regulation of Connexin32 by ephrin receptors and T-cell protein-tyrosine phosphatase. J Biol Chem. 2019;294:341–50. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These modifications diversify the intracellular sites available for protein interactions, allowing different complexes to be formed and altering the transmitted signal.

    “These modifications diversify the intracellular sites available for protein interactions, allowing different complexes to be formed and altering the transmitted signal [169, 255].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [169] Warnet XL, Krog HB, Sevillano-Quispe OG, Poulsen H, Kjaergaard M. The C-terminal domains of the NMDA receptor: how intrinsically disordered tails affect signaling, plasticity, and disease. Eur J Neurosci. 2020. https://doi.org/10.1111/EJN.14842. source

      Not checked in the free run.

    • cites [255] Enz R. Structure of metabotropic glutamate receptor C-terminal domains in contact with interacting proteins. Front Mol Neurosci. 2012;5:52.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ERα contains an intrinsically disordered transactivation domain (AF1) in its N terminus, activity of which is regulated by phosphorylation and associated phosphorylation-coupled proline isomerization.

    “In line with this hypothesis, there are several studies showing that ERα contains an intrinsically disordered transactivation domain (AF1) in its N terminus [244], activity of which is regulated by phosphorylation and associated phosphorylation-coupled proline isomerization [245, 246].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [244] Peng Y, Cao S, Kiselar J, Xiao X, Du Z, Hsieh A, et al. A metastable contact and structural disorder in the estrogen receptor transactivation domain. Structure. 2019;27:229–40. source

      Not checked in the free run.

    • cites [245] Rajbhandari P, Finn G, Solodin NM, Singarapu KK, Sahu SC, Markley JL, et al. Regulation of estrogen receptor α N-terminus conformation and function by peptidyl prolyl isomerase Pin1. Mol Cell Bol. 2012;32:445–57. source

      Not checked in the free run.

    • cites [246] Rajbhandari P, Szatkowski Ozers M, Solodin NM, Warren CL, Alarid ET. Peptidylprolyl isomerase Pin1 directly enhances the DNA binding functions of Estrogen Receptor α. J Biol Chem. 2015;290:13749–62. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Phosphorylation in the connexin C-terminal region regulates protein interaction, channel assembly, channel degradation, and metabolic and electrical coupling, and thus controls trafficking through the channel.

    “Phosphorylation in this region regulates protein interaction, channel assembly, channel degradation, and metabolic and electrical coupling, and thus controls trafficking through the channel [253].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [253] Sorgen PL, Trease AJ, Spagnol G, Delmmar M, Nielsen MS. Protein-protein interactions with Connexin 43” Regulation and function. Int J Mol Sci. 2018;19:1428. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vitro, interactions with metal ions, other proteins, and sodium dodecyl sulfate induce the formation of limited structure for some dehydrins, which can be transiently stable in vivo.

    “In vitro, interactions with metal ions, other proteins, and sodium dodecyl sulfate induce the formation of limited structure for some dehydrins [228, 229], which can be transiently stable in vivo [230].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [228] Yu ZY, Wang X, Zhang LS. Structural and functional dynamics of dehydrins: a plant protector protein under abiotic stress. Int J Mol Sci. 2018;19:3420. source

      Not checked in the free run.

    • cites [229] Yokoyama T, Ohkubo T, Kamiya K, Hara M. Cryoprotective activity of Arabidopsis KS-type dehydrin depends on the hydrophobic amino acids of the two active segments. Arch Biochem Biophys. 2020;691:108510. source

      Not checked in the free run.

    • cites [230] Murvai N, Kalmar L, Szalaine Agoston B, Szabo B, Tantos A, Csikos G, et al. Interplay of structural disorder and short binding elements in the cellular chaperone function of plant dehydrin ERD14. Cells. 2020;9:1856. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The CTDs of both glutamate receptors are alternatively spliced and post-translationally modified (phosphorylation and SUMOylation for metabotropic receptors, phosphorylation and palmitoylation for ionotropic receptors).

    “The CTDs of both receptors are alternatively spliced, and post-translationally modified (phosphorylation and SUMOylation for metabotropic receptors, phosphorylation and palmitoylation for ionotropic receptors) [169, 255].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [169] Warnet XL, Krog HB, Sevillano-Quispe OG, Poulsen H, Kjaergaard M. The C-terminal domains of the NMDA receptor: how intrinsically disordered tails affect signaling, plasticity, and disease. Eur J Neurosci. 2020. https://doi.org/10.1111/EJN.14842. source

      Not checked in the free run.

    • cites [255] Enz R. Structure of metabotropic glutamate receptor C-terminal domains in contact with interacting proteins. Front Mol Neurosci. 2012;5:52.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A mutation in the BDNF prodomain, V66M, is present in 20% of humans and increases the occurrence of anxiety disorders, depression, memory deficits, and impairs recovery after traumatic brain injury.

    “Interestingly, a mutation in the prodomain, V66M, is present 20% of humans and increases the occurrence of anxiety disorders, depression, memory deficits, and impairs recovery after traumatic brain injury (reviewed in [248]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [248] Wang J, Anastasia A, Bains H, Giza JI, Clossey DG, Deng J, et al. Zinc induced structural changes in the intrinsically disordered BDNF Met prodomain confer synaptic elimination. Metallomics. 2020;12:1208. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Many cellular processes regulated by chemical stimuli, such as proliferation, differentiation, motility, and survival, are also influenced by the mechanical properties of the substrate supporting the cells.

    “Many cellular processes that are regulated by chemical stimuli, such as proliferation, differentiation, motility, and survival, are also influenced by the mechanical properties of the substrate supporting the cells [221].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [221] Janmey PA, Miller RT. Mechanisms of mechanical signaling in development and disease. J Cell Sci. 2011;124:9–18. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dehydrins protect plants from dehydration and from cold.

    “Dehydrins protect plants from dehydration and from cold [228].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [228] Yu ZY, Wang X, Zhang LS. Structural and functional dynamics of dehydrins: a plant protector protein under abiotic stress. Int J Mol Sci. 2018;19:3420. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dehydrins are a family of intrinsically disordered proteins that act as effectors whose expression is induced by signaling pathways that sense abiotic stresses, such as cold or drought.

    “Dehydrins are a family of intrinsically disordered proteins that act as effectors whose expression is induced by signaling pathways that sense abiotic stresses, such as cold or draught.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [228] Yu ZY, Wang X, Zhang LS. Structural and functional dynamics of dehydrins: a plant protector protein under abiotic stress. Int J Mol Sci. 2018;19:3420. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Despite the large variety of signal transmission mechanisms used, IDRs/IDPs act as crucial components in each of the autocrine, juxtacrine, intracrine, paracrine, and endocrine categories.

    “Despite the large variety of signal transmission mechanisms used, IDRs/IDPs act as crucial components in each of these different categories.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Wnt family signaling proteins are both glycosylated and palmitoylated and are universal across multicellular members of the animal kingdom but absent in single cell members, with a few paralogues in sponges and with 19 paralogues in humans.

    “The Wnt family signaling proteins are both glycosylated and palmitoylated and are universal across multicellular members of the animal kingdom but absent in single cell members, with a few paralogues in sponges and with 19 paralogues in humans [257, 258, and The Wnt Homepage (stanford.edu)].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [257] Nusse R, Clevers H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell. 2017;169:985–99. source

      Not checked in the free run.

    • cites [258] Eubelen M, Bostaille N, Cabochette P, Gauquier A, Tebabi P, Dumitru AC, et al. A molecular mechanism for Wnt ligand-specific signaling. Science. 2018;361:eaat1178. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The BDNF proprotein must be cleaved to form an intrinsically disordered N-terminal prodomain and a structured C-terminal protein which dimerizes to form mature BDNF (mBDNF), both of which are secreted and have activity.

    “The BDNF proprotein must be cleaved to form an intrinsically disordered N-terminal prodomain, and a structured C-terminal protein which dimerizes to form mature BDNF (mBDNF), both of which are secreted and have activity [248].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [248] Wang J, Anastasia A, Bains H, Giza JI, Clossey DG, Deng J, et al. Zinc induced structural changes in the intrinsically disordered BDNF Met prodomain confer synaptic elimination. Metallomics. 2020;12:1208. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Selectivity of Wnt-Fz interactions can be achieved by formation of larger Wnt-receptor complexes, in which Fz interaction is mediated by conserved Wnt residues, and divergent, intrinsically disordered regions of the same Wnt bind additional receptors, such as Reck.

    “This selectivity can be achieved by formation of larger Wnt-receptor complexes, in which Fz interaction is mediated by conserved Wnt residues, and divergent, intrinsically disordered regions of the same Wnt bind additional receptors, such as Reck [258].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [258] Eubelen M, Bostaille N, Cabochette P, Gauquier A, Tebabi P, Dumitru AC, et al. A molecular mechanism for Wnt ligand-specific signaling. Science. 2018;361:eaat1178. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The CadC protein is a pH-responsive one-component signaling system composed of an N-terminal winged helix-turn-helix DNA binding domain, followed by a 50 amino acid intrinsically disordered region linking to a single transmembrane helix and ending in a C-terminal pH sensing domain which extends into the periplasm.

    “For instance, the CadC protein is a pH-responsive one-component signaling system composed of an N-terminal winged helix-turn-helix DNA binding domain, followed by a 50 amino acid intrinsically disordered region linking to a single transmembrane helix and ending in a C-terminal pH sensing domain which extends into the periplasm [161].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [161] Buchner S, Schlundt A, Lassak J, Sattler M, Jung K. Structural and functional analysis of the signal-transducing linker in the pH-responsive one-component system CadC of Escherichia coli. J Mol Biol. 2015;427:2548–61. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Wnt/β-catenin signaling must be strictly controlled because its dysregulation, caused by different stimuli and many mutations, leads to alterations in cell proliferation, apoptosis, inflammation-associated cancer, or stem cell proliferation/self-renewal for embryonic and adult stem cells.

    “Due to its prominent physiological function, the Wnt/β-catenin signaling must be strictly controlled because its dysregulation, which is caused by different stimuli and also by many different mutations that lead to alterations in cell proliferation, apoptosis, inflammation-associated cancer or alterations in stem cell proliferation or self-renewal, for both embryonic and various types of adult”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [257] Nusse R, Clevers H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell. 2017;169:985–99. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The two kinases and β-catenin bind to Axin's long intrinsically disordered region, thereby connecting structured proteins with flexible linkers.

    “The two kinases and β-catenin bind to Axin’s long intrinsically disordered region, thereby connecting structured proteins with flexible linkers.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [259] Xue B, Romero PR, Noutsou M, Maurice MM, Rüdiger SG, William AM Jr, et al. Stochastic machines as a colocalization mechanism for scaffold protein function. FEBS Lett. 2013;587:1587–91. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Upon ligand binding, the transmembrane helix re-arranges and EGFR forms active dimers.

    “Upon ligand binding, the transmembrane helix re-arranges and EGFR forms active dimers [284, 285].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [284] Arkhipov A, Shan Y, Das R, Endres NF, Eastwood MP, Wemmer DE, et al. Architecture and membrane interactions of the EGF receptor. Cell. 2013;152:557–69. source

      Not checked in the free run.

    • cites [285] Endres NF, Das R, Smith AW, Arkhipov A, Kovacs E, Huang Y, et al. Conformation coupling across the plasma membrane in activation of the EGF receptor. Cell. 2013;152:543–56. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Phosphorylation modifications signal β-catenin's subsequent ubiquitination, which also occurs primarily within IDRs.

    “The phosphorylation modifications signal β-catenin’s subsequent ubiquitination, which also occurs primarily within IDRs [261].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [261] Radivojac P, Vacic V, Haynes C, Cocklin RR, Mohan A, Heyen JW, et al. Identification, analysis, and prediction of protein ubiquitination sites. Proteins. 2010;78:365–80. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Intrinsic disorder may be present, and provide regulatory opportunities, for any of the following steps: ligand production, ligand activity, ligand bioavailability, receptor structure, intracellular transmission, termination/intracellular trafficking, and effector proteins.

    “Intrinsic disorder may be present, and provide regulatory opportunities, for any of the following steps: ligand production, ligand activity, ligand bioavailability, receptor structure, intracellular transmission, termination/intracellular trafficking, and effector proteins (Fig. 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A 55 residue segment of axin containing binding sites for both β-catenin and GSK3b has the biophysical properties of an unstructured protein, in agreement with predictions of disorder.

    “Laboratory experiments show that a 55 residue segment of axin containing binding sites for both β-catenin and GSK3b has the biophysical properties of an unstructured protein [263], which is in agreement with the predictions of disorder on this protein.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [263] Noutsou M, Duarte AM, Anvarian Z, Didenko T, Minde DP, Kuper I, et al. Critical scaffolding regions of the tumor suppressor Axin1 are natively unfolded. J Mol Biol. 2011;405:773–86. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Heparin binds more than 400 proteins, including many involved in cell signaling.

    “Heparin binds > 400 proteins, including many involved in cell signaling [279].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [279] Peysselon F, Richard-Blum S. Heparin-protein interactions: from affinity and kinetics to biological roles. Application to an interaction network regulating angiogenesis. Matrix Biol. 2014;35:73–81. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Random movements of the bound proteins enabled by the flexible linkers bring about frequent kinase-substrate collisions, which lead to efficient phosphorylation.

    “Random movements of the bound proteins enabled by the flexible linkers bring about frequent kinase-substrate collisions, which, in turn, lead to efficient phosphorylation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [259] Xue B, Romero PR, Noutsou M, Maurice MM, Rüdiger SG, William AM Jr, et al. Stochastic machines as a colocalization mechanism for scaffold protein function. FEBS Lett. 2013;587:1587–91. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Since intrinsically disordered regions are highly prevalent in transcription factors, intrinsic disorder is a major factor in regulating the production of cell signals.

    “Since intrinsic disordered regions are highly prevalent in transcription factors [273–277], intrinsic disorder is a major factor in regulating the production of cell signals.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [273] Brodsky S, Jana T, Mittelman K, Chapal M, Kumar DK, Carmi M, et al. Intrinsically disordered regions direct transcription factor in vivo binding specificity. Mol Cell. 2020;79:459–71. source

      Not checked in the free run.

    • cites [274] Clark S, Myers J, King A, Fiala R, Novacek J, Pearce G, et al. Multivalency regulates activity in an intrinsically disordered transcription factor. eLife. 2018;2018(7):e36258. source

      Not checked in the free run.

    • cites [275] Liu J, Perumal NB, Oldfield CJ, Su EW, Uversky VN, Dunker AK. Intrinsic disorder in transcription factors. Biochemistry. 2006;45:6873–88. source

      Not checked in the free run.

    • cites [276] Tarczewska A, Greb-Markiewicz B. The significance of the intrinsically disordered regions for the functions of the bHLH transcription factors. Int J Mol Sci. 2019;20:5306. source

      Not checked in the free run.

    • cites [277] Vuzman D, Levy Y. Intrisically disordered regions as affinity tuners in protein-DNA interactions. Mol BioSyst. 2012;8:47–57. source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    The resultant molecular complex Wnt-Fzd-LRP5/6-Dvl forms a structural region for Axin interaction that disrupts Axin-mediated phosphorylation/degradation of β-catenin, allowing it to stabilize and accumulate in the nucleus where it activates expression of multiple Wnt-dependent genes.

    “The resultant molecular complex Wnt-Fzd-LRP5/6-Dvl forms a structural region for Axin interaction that disrupts Axin-mediated phosphorylation/degradation of the transcriptional co-activator β-catenin, thereby allowing it to stabilize and accumulate in the nucleus where it activates the expression of multiple Wnt-dependent genes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The cytoplasmic domain of LRP5/6 is disordered, reflecting disorder in the cytoplasmic domains of other single pass membrane proteins and like most other segments that undergo phosphorylation.

    “This binding promotes recruitment of the scaffolding protein disheveled (Dvl), which results in the phosphorylation of the cytoplasmic domain of LRP5/6, a domain whose disorder [264, 265] reflects disorder in the cytoplasmic domains of other single pass membrane proteins [266] and like most other segments that undergo phosphorylation [41, 265].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [264] Harnoš J, Cañizal MCA, Jurásek M, Kumar J, Holler C, Schambony A, et al. Dishevelled-3 conformation dynamics analyzed by FRET-based biosensors reveals a key role of casein kinase 1. Nat Commun. 2019;10:1804. source

      Not checked in the free run.

    • cites [265] Hanáková K, Bernatík O, Kravec M, Micka M, Kumar J, Harnoš J, et al. Comparative phosphorylation map of Dishevelled 3 links phosphor-signatures to biological outputs. Cell Commun Signal. 2019;17:170. source

      Not checked in the free run.

    • cites [266] Burgi J, Xue B, Uversky VN, van der Groot G. Intrinsic disorder in transmembrane proteins: roles in signaling and topology prediction. PLoS ONE. 2016;11:e0158594. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Overall, these data show that the phosphorylation rate enhancement occurs by the binding of both the kinase and the substrate to a single flexible tether and not by activation resulting from the binding of axin to the enzyme or the substrate.

    “Overall, these data show that the phosphorylation rate enhancement occurs by the binding of both the kinase and the substrate to a single flexible tether and not by activation resulting from the binding of axin to the enzyme or the substrate [263].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [263] Noutsou M, Duarte AM, Anvarian Z, Didenko T, Minde DP, Kuper I, et al. Critical scaffolding regions of the tumor suppressor Axin1 are natively unfolded. J Mol Biol. 2011;405:773–86. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gab2 is an LMD protein that transmits signals from integrins, receptor tyrosine kinases, cytokine receptors, multi-chain immune recognition receptors, and G protein-coupled receptors, and is required to activate Akt, Ras/Raf, Rac, c-fos, Jak/Stat, Rac, and other intracellular transducers.

    “Gab2 is a type of LMD protein that operates as part of many signaling pathways [308, 311] and transmits signals from integrins, receptor tyrosine kinases, cytokine receptors, multi-chain immune recognition receptors, and G protein-coupled receptors, and is required to activate Akt, Ras/Raf, Rac, c-fos, Jak/Stat, Rac, and a host of other intracellular transducers [308, 311, 312].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [308] Simister PC, Feller SM. Order and disorder in large multi-site docking proteins of the Gab family—implications for signaling complex formation and inhibitor design strategies. Mol BioSyst. 2012;8:33–46. source

      Not checked in the free run.

    • cites [311] Hunzicker-DunnME Lopez-Biladeau B, Law NC, Fiedler SE, Carr DW, Maizels ET. PKA and GAB2 play central roles in the FSH signaling pathways to PI3K and AKT in ovarian granulosa cells. Proc Natl Acad Sci USA. 2012;109:E2979–88. source

      Not checked in the free run.

    • cites [312] Wöhrle FU, Daly RJ, Brummer T. Function, regulation and pathological roles of the Gab/DOS docking proteins. Cell Commun Signaling. 2009;7:22. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Similar regulatory mechanisms have been established for G-protein coupled receptors.

    “Similar regulatory mechanisms have been established for G-Protein Coupled Receptors (Fig. 5), which were recently reviewed by Zhou et al. [39].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Zhou J, Zhao S, Dunker AK. Intrinsically disordered proteins link alternative splicing and post-translational modifications to complex cell signaling and regulation. J Mol Biol. 2018;430:2342–59. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LMDs bind to integrate signals from multiple pathways and coordinate the downstream response.

    “Thus, LMDs bind to both integrate signals from multiple pathways and coordinate the downstream response [27, 307, 308].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [27] Kreiger JM, Fusco G, Lewitzky M, Simister PC, Marchant J, Camilloni C, et al. Conformational recognition of an intrinsically disordered protein. Biophys J. 2014;106:1771–9. source

      Not checked in the free run.

    • cites [307] McDonald CB, Seldeen KL, Deegan BJ, Bhat V, Farooq A. Assembly of the Sos1-Grb2-Gab1 ternary signaling complex is under allosteric control. Arch Biochem Biophys. 2010;494:216–25. source

      Not checked in the free run.

    • cites [308] Simister PC, Feller SM. Order and disorder in large multi-site docking proteins of the Gab family—implications for signaling complex formation and inhibitor design strategies. Mol BioSyst. 2012;8:33–46. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Conformational entropy plays an important role in talin binding to β tails of integrins, with a preformed helix binding more readily than a disordered one.

    “The α-helical propensity, dynamics, and affinity in the β tails of integrins strongly suggest that conformational entropy plays an important role in Talin binding, with a preformed helix binding more readily than a disordered one [299].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [299] Anthis NJ, Wegener KL, Critchley DR, Campbell ID. Structural diversity in integrin/talin interactions. Structure. 2010;18:1654–66. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Integrins mediate two-way communication between the cell interior and the extracellular matrix and regulate ion channels, growth factor receptors, and cytoplasmic kinases.

    “Integrins not only mediate two-way communication between the cell interior and the extracellular matrix, but they also regulate ion channels, growth factor receptors, and the activity of cytoplasmic kinases [291].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [291] Giancotti FG, Ruoslahti E. Integrin signaling. Science. 1999;285:1028–33. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The disorder in the Ras tail enables PTMs that add lipids and other groups to the tail, regulating membrane anchoring, domain positioning, auto-inhibition, effector protein binding, and ultimately Ras-mediated signaling.

    “The disorder in the tail enables the occurrence of PTMs that add lipids and other groups to the tail, regulating membrane anchoring, domain positioning, auto-inhibition, effector protein binding, and, ultimately, Ras-mediated signaling [320, 321].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [320] Nussinov R, Jang H, Tsai C-J, Liao T-J, Li S, Fushman D, et al. Intrinsic protein disorder in oncogenic KRAS signaling. Cell Mol Life Sci. 2017;74:3245–61. source

      Not checked in the free run.

    • cites [321] Abdelkarim H, Banerjee A, Grudzien P, Leschinsky N, Abushaer M, Gaponenko V. The hypervariable region of K-Ras4B governs molecular recognition and function. Int J Mol Sci. 2019;20:5718. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This conformational change promotes autophosphorylation, and hence activation, of the two tyrosine kinase domains.

    “This conformational change promotes autophosphorylation, and hence activation, of the two tyrosine kinase domains [281].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [281] Cornish J, Chamerlain SG, Own D, Mott HR. Intrinsically disordered proteins and membranes: a marriage of convenience for cell signaling? Biochem Soc Trans. 2020;48:2669–89. source

      Not checked in the free run.

70 of 70

  • The paper relies on this without support.

    The examples reviewed are representative of cell signaling pathways generally.

    “IDPs/IDRs are uniquely suited to solving these problems, as demonstrated by several examples detailed in this review (Table 1).”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Disordered proteins and regions are characterized by broad and heterogeneous ensembles with small differences in relative conformational stabilities and low barriers.

    “Disordered proteins (regions) are characterized by broad and heterogeneous ensembles where the differences in the relative conformational stabilities are small, or even minor and the barriers are low.”

    From AlphaFold, Artificial Intelligence (AI), and Allostery (2022) · cites this paper as [132]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Glucocorticoid receptor disorder is assigned to opposite termini

    Minor

    Figure 3 attributes regulation of the glucocorticoid receptor to an intrinsically disordered C-terminal tail, whereas Figure 2 identifies the N-terminal domain as mostly disordered and the C-terminal region as the ligand-binding domain.

  • Paracrine signaling switches from glutamate to glutamine

    Minor

    The paragraph identifies glutamate as the neurotransmitter and says it binds the receptors, but describes the downstream response as occurring after glutamine binding. Glutamate and glutamine are different molecules.

  • Wnt discussion points to a figure about the glucocorticoid receptor

    Minor

    The Wnt discussion cites Figure 2, but Figure 2 depicts the glucocorticoid receptor. The Wnt signaling diagram is labeled Figure 4.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 4

  1. Dunker AK, Obradovic Z, Romero P, Kissinger C, Villafranca JE. On the importance of being disordered. Protein Data Bank Q Newsl. 1997;81:3–5.
  2. Daughdrill GW, Pielak GJ, Uversky VN, Cortese MS, Dunker AK. Natively disordered proteins. In: Buchner J, Kiefhaber T, editors. Handbook of protein folding. Weinheim: Wiley, Verlag GmbH & Co KGaA; 2005. p. 271–353.
  3. Schulz GE. Nucleotide binding proteins. In: Balaban M, editor. Molecular mechanism of biological recognition. New York: Elsevier/North-Holland Biomedical Press; 1979. p. 79–94.
  4. Meek DW, Anderson CW. Post-translational modiication of p53” cooperative integrators of function. Cold Spring Harb Perspect Biol. 2009;1:a000950.

Cited by

Sorted by citations

Related

Authors
Bondos, S. E., Dunker, A. K., & Uversky, V. N.
Affiliations
  • Texas A&M Health Science Center (US)
  • Indiana University Indianapolis (US)
  • Russian Academy of Sciences (RU)
Corresponding author
Bondos, Sarah E.
ORCID
Venue
Cell Communication and Signaling
Publisher
Springer Science and Business Media LLC
Published
2022-02-17
Volume
20
Issue
1
Pages
20-20
ISSN
1478-811X (ISSN-L)
DOI
10.1186/s12964-022-00821-7
PMC
PMC8851865
OpenAlex
W4212940766
Semantic Scholar
fe30172eab9a4c8b8f27061cb9011b6e6d6de4c2
Cited by
222
References
330
Citations by year
2026: 50 · 2025: 62 · 2024: 45 · 2023: 46 · 2022: 18 · 2021: 1
FWCI
4.45
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Communication and Signaling (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by)
  • Digital Commons - University of South Florida (University of South Florida) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (GM099827-06)
  • National Institute on Aging (RF1 AG055088)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
intrinsically disordered proteins, intrinsically disordered regions, signal transduction, protein-protein interaction, ligand binding, receptor signaling, transducers, signal amplification, signal termination, autocrine signaling, paracrine signaling, hormone signaling, juxtacrine signaling, intracrine signaling, intercellular communication
MeSH terms
Animals, Cell Communication, Signal Transduction, Intrinsically Disordered Proteins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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