Cited by 156Protein Structure and DynamicsProtein Interaction Studies and Fluorescence Analysis14-3-3 protein interactions

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Interactions by Disorder – A Matter of Context

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Bugge, Katrine, Brakti, Inna, Fernandes, Catarina B., Dreier, Jesper E., Lundsgaard, Jeppe E., Olsen, Johan G., Skriver, Karen, Kragelund, Birthe B.·2020·Frontiers in Molecular Biosciences

DOI 10.3389/fmolb.2020.00110PMC PMC7308724

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Abstract

Living organisms depend on timely and organized interactions between proteins linked in interactomes of high complexity. The recent increased precision by which protein interactions can be studied, and the enclosure of intrinsic structural disorder, suggest that it is time to zoom out and embrace protein interactions beyond the most central points of physical encounter. The present paper discusses protein-protein interactions in the view of structural disorder with an emphasis on flanking regions and contexts of disorder-based interactions. Context constitutes an overarching concept being of physicochemical, biomolecular, and physiological nature, but it also includes the immediate molecular context of the interaction. For intrinsically disordered proteins, which often function by exploiting short linear motifs, context contributes in highly regulatory and decisive manners and constitute a yet largely unrecognized source of interaction potential in a multitude of biological processes. Through selected examples, this review emphasizes how multivalency, charges and charge clusters, hydrophobic patches, dynamics, energetic frustration, and ensemble redistribution of flanking regions or disordered contexts are emerging as important contributors to allosteric regulation, positive and negative cooperativity, feedback regulation and negative selection in binding. The review emphasizes that understanding context, and in particular the role the molecular disordered context and flanking regions take on in protein interactions, constitute an untapped well of energetic modulation potential, also of relevance to drug discovery and development.

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FIGURE 1 Context contribution to disorder-based protein interactions. (A) A binding region within an IDP illustrated by a single SLiM. The binding region is embedded in a disordered chain in which additional features are present that can affect the interaction. The red spheres with helical structures illustrate that the IDR may be part of a modular protein and connected to folded domains. (B) Flanking regions can modulate IDP binding by, e.g., charge complementarity, secondary structure formation, and phosphorylation (illustrated by an encircled P). (C) Binding regions distant to the central binding site can contextually modulate binding. (D) Negative selection by means of mismatching flanking region properties. (E) Allosteric regulation through the flanking region via conformational changes in the folded partner (red) induced by IDP binding. This may also lead to partner selection as indicated by the second SLiM (in orange) leaving the binding site. (F) Allosteric regulation by ensemble redistribution of the disordered chain, here illustrated by changes in the degree of compaction. (G) Avidity by additional SLiMs or binding sites within the disordered chain binding outside the (or one of the) central contact point(s) (orange). (H) Multivalency by additional SLiMs or binding sites binding to different proteins resulting in dynamic binding illustrated by three chains with different colored SLiMs. (I) Contextual allovalency. Several SLiMs within the same disordered chain bind to the same binding site on the target protein – one at the time – and increase affinity through allovalency effects, here illustrated by three different chains of the ensemble, (J) Liquid-liquid phase separation (LLPS) by multiple SLiMs (top droplet and top zoom) or by SLiM:domain interactions (bottom droplet and bottom zoom). The red spheres represent a folded binding partner in all figures.CC BY · PubMed Central

FIGURE 2 Context and time. The C-terminal conformational switch, flanking a central helical region involved in interactions with CBP/p300 and CRY1 in the disordered transcriptional activation domain of BMAL1, involves cis/trans isomerization around a Trp-Pro imide bond, which modulates circadian timing. Locking the switch into the trans conformation results in a shorter circadian period compared to the wild-type, while inhibiting cyclophilins, which accelerate the interconversion between isomers, lengthens the circadian period in a dose-dependent manner (Gustafson et al., 2017).CC BY · PubMed Central

FIGURE 3 Context of the SLiM flanking regions fine tunes affinity. Electrostatic surface potential mapped onto the surface of the separated components of the p21-PCNA complex showing the outwards facing surface of one PCNA monomer of the trimer and the surface of a p21-peptide (PDB code 1AXC). Charge complementarity between positive charges in the flanking regions (orange) of the p21 PIP-degron motif (gray) and the highly negatively charged PCNA patches surrounding the binding pocket, modulates the binding affinity over four orders of magnitude. The figure was adapted from Figure 6C, originally published in Prestel et al. (2019), Cell. Mol. Life Sci., 2019.CC BY · PubMed Central

FIGURE 4 Modulation of binding by chain dynamics. The flexible nature of HIF-1α bound to TAZ1 allows the transactivation domain of CITED2 to gain access to TAZ1 through its N-terminal region. This results in the formation of a ternary complex which induces an allosteric conformational change in TAZ1, disfavoring/out-competing HIF-1α binding. The CITED2 LPEL-SLiM and flanking αA helical region act cooperatively to displace HIF-1α from the shared binding site for the LP(Q/E)L SLiM and the restricted motions adopted in the bound state minimize competition for binding. In this schematic illustration, TAZ1 is depicted in red, HIF-1α is dark gray and the bound LP(Q/E)L SLiM is light gray with a dashed outline. The SLiM-flanking regions in CITED2 are shown in orange. Adapted from Figure 4, originally published in Berlow et al. (2017).CC BY · PubMed Central

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The MYC oncoprotein directly interacts with its chromatin cofactor PNUTS to recruit PP1 phosphatase
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“To determine whether PNUTS(1-148) interacted directly with MYC, we initially focused our analysis on the six highly conserved and regulatory MYC Box (MB) regions.”
Influential
Protein Condensation, Cellular Organization, and Spatiotemporal Regulation of Cytoplasmic Properties
van Tartwijk, F. W., & Kaminski, C. F. (2022) · Advanced Biology · doi:10.1002/adbi.202101328 · Cited by 28
Predicting the effect of disordered linkers on effective concentrations and avidity with the “C calculator” app
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Ensemble description of the intrinsically disordered N-terminal domain of the Nipah virus P/V protein from combined NMR and SAXS
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“The context of αα -hub interactions is multifacial, including the disordered SLiM context of the partners, the modular protein scaffold of the hub, as well as the environment (139).”
NAP1L1 and NAP1L4 Binding to Hypervariable Domain of Chikungunya Virus nsP3 Protein Is Bivalent and Requires Phosphorylation
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“Besides demonstrating unusual 386 physical characteristics, IDPs can interact with multiple proteins, mediate formation of 387 large complexes and thus, are critically involved in numerous cellular processes (46-49).”
Background
The bacterial DNA sliding clamp, β-clamp: structure, interactions, dynamics and drug discovery
Simonsen, S., Søgaard, C. K., Olsen, J. G., Otterlei, M., & Kragelund, B. B. (2024) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-024-05252-w · Cited by 23
“However, flanking sequence regions outside the CBM as well as contacts made from other (folded) parts of the ligand, can impact binding affinity, conformation, and function as seen for other SLiMs [80].”
Structural Insights into the Interaction of the Intrinsically Disordered Co-activator TIF2 with Retinoic Acid Receptor Heterodimer (RXR/RAR)
Sénicourt, L., le Maire, A., Allemand, F., Carvalho, J. E., Guée, L., Germain, P., Schubert, M., Bernadó, P., Bourguet, W., & Sibille, N. (2021) · Journal of Molecular Biology · doi:10.1016/j.jmb.2021.166899 · Cited by 24
Direct prediction of intermolecular interactions driven by disordered regionsPreprint
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Flanking Disorder of the Folded αα-Hub Domain from Radical Induced Cell Death1 Affects Transcription Factor Binding by Ensemble Redistribution
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Location, location, location: Protein kinase nanoclustering for optimised signalling output
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An extended interaction site determines binding between AP180 and AP2 in clathrin mediated endocytosis
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Proteome-scale characterisation of motif-based interactome rewiring by disease mutations
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“…likely to result in the reduction or enhancement of af ﬁ nity, there is a growing literature reporting on the contribution of non-consensus residues in motif instances (wild-card positions) and of motif-ﬂ anking regions to the af ﬁ nity of interactions (Karlsson et al, 2022; Bugge et al, 2020).”
Macromolecular Crowding Induces a Binding Competent Transient Structure in Intrinsically Disordered Gab1
Gruber, T., Lewitzky, M., Machner, L., Weininger, U., Feller, S. M., & Balbach, J. (2021) · Journal of Molecular Biology · doi:10.1016/j.jmb.2021.167407 · Cited by 21
Role of charges in a dynamic disordered complex between an IDP and a folded domain
Bugge, K., Sottini, A., Ivanović, M. T., Buus, F. S., Saar, D., Fernandes, C. B., Kocher, F., Martinsen, J. H., Schuler, B., Best, R. B., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-58374-5 · Cited by 20
“Reviewer #2 (Remarks to the Author) In the reviewed manuscript, Bugge et al. probe the dynamic, electrostatic interactions between prothymosin alpha (an IDP) and the small, folded domain of H1.”
Use of AI-methods over MD simulations in the sampling of conformational ensembles in IDPs
Sil, S., Datta, I., & Basu, S. (2025) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2025.1542267 · Cited by 22
Conformational Changes in the Negative Arm of the Circadian Clock Correlate with Dynamic Interactomes Involved in Post-Transcriptionally Regulated Processes
Pelham, J. F., Mosier, A. E., Altshuler, S. C., Rhodes, M. L., Kirchhoff, C. L., Fall, W. B., Mann, C., Baik, L. S., Chiu, J. C., & Hurley, J. (2021) · Cell Reports · doi:10.1016/j.celrep.2023.112376 · Cited by 19
Sequence and chemical specificity define the functional landscape of intrinsically disordered regions
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“The importance of context in relation to motif function has been seen in other systems 61,82,110 .”
Evolution of SLiM-mediated hijack functions in intrinsically disordered viral proteins
Glavina, J., Palópoli, N., & Chemes, L. B. (2022) · Essays in Biochemistry · doi:10.1042/ebc20220059 · Cited by 15
“The close inspection of host and viral SLiMs indicates that fine-tuning of binding affinity and specificity occurs at multiple levels [101] which include changes in core [67], wildcard [70,102] and flanking [72,103] residues (Figure 4) as well as conformational preferences such as secondary…”
Background
Intrinsic disorder and flexibility in proteins: a challenge for structural biology and drug design
Zanotti, G. (2023) · Crystallography Reviews · doi:10.1080/0889311x.2023.2208518 · Cited by 16
“All these factors are analysed and discussed in reference [86], and examples are reported.”
Background
Allosteric control of dynamin-related protein 1 through a disordered C-terminal Short Linear Motif
Pérez-Jover, I., Rochon, K., Hu, D., Mahajan, M. K., Mohan, P. M., Santos-Pérez, I., Gisasola, J. O., Galvez, J. M. M., Agirre, J., Qi, X., et al. (2024) · Nature Communications · doi:10.1038/s41467-023-44413-6 · Cited by 15
“1a, b) that, unlike other IDRs in Drp1, is highly conserved among metazoans (Supplementary Fig.”
BackgroundInfluential
Design of functional intrinsically disordered proteins
Garg, A., Foutel, N. S. G., Gielnik, M. B., & Kjærgaard, M. (2024) · Protein Engineering Design and Selection · doi:10.1093/protein/gzae004 · Cited by 15
Synergies of Single Molecule Fluorescence and NMR for the Study of Intrinsically Disordered Proteins
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Structural basis for tunable affinity and specificity of LxCxE-dependent protein interactions with the retinoblastoma protein family
Putta, S., Álvarez, L., Lüdtke, S., Sehr, P. A., Müller, G. A., Fernandez, S. M., Tripathi, S. M., Lewis, J., Gibson, T. J., Chemes, L. B., et al. (2022) · Structure · doi:10.1016/j.str.2022.05.019 · Cited by 16
A context-dependent and disordered ubiquitin-binding motif
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“In some cases, a SLiM alone may not represent the entire binding event, and the context of the disordered chain can impact the interaction both positively and negatively [25, 71].”
Ubiquitin Interacting Motifs: Duality Between Structured and Disordered Motifs
Lambrughi, M., Maiani, E., Fas, B. A., Shaw, G. S., Kragelund, B. B., Lindorff‐Larsen, K., Teilum, K., Invernizzi, G., & Papaleo, E. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.676235 · Cited by 13
“Although individual SLiMs are short and mostly participate in transient interactions, they are essential to protein binding specificity and function (Bugge et al., 2020; Kumar et al., 2020).”
Background
Functional roles and cancer variants of the bifunctional glycosylase NEIL2
Hua, A., & Sweasy, J. B. (2023) · Environmental and Molecular Mutagenesis · doi:10.1002/em.22555 · Cited by 12
“This particular missense mutation occurs in the NEIL2 disordered region, which is known to participate in protein – protein interactions (Bugge et al., 2020).”
The MDMX Acidic Domain Uses Allovalency to Bind Both p53 and MDMX
Fenton, M. J., Borcherds, W. M., Chen, L., Anbanandam, A., Levy, R., Chen, J., & Daughdrill, G. W. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167844 · Cited by 12
Disordered clock protein interactions and charge blocks turn an hourglass into a persistent circadian oscillator
Jankowski, M. S., Griffith, D., Shastry, D. G., Pelham, J. F., Ginell, G. M., Thomas, J., Karande, P., Holehouse, A. S., & Hurley, J. M. (2024) · Nature Communications · doi:10.1038/s41467-024-47761-z · Cited by 23
Protein binding and folding through an evolutionary lens
Jemth, P. (2025) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2024.102980 · Cited by 11
MUL1‐RING recruits the substrate, p53‐TAD as a complex with UBE2D2–UB conjugate
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Self-Diffusive Properties of the Intrinsically Disordered Protein Histatin 5 and the Impact of Crowding Thereon: A Combined Neutron Spectroscopy and Molecular Dynamics Simulation Study
Fagerberg, E., Lenton, S., Nylander, T., Seydel, T., & Skepö, M. (2022) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.1c08976 · Cited by 11
The Structure of the Drp1 Lattice on Membrane
Peng, R., Rochon, K., Hutson, A. N., Stagg, S. M., & Mears, J. A. (2025) · Journal of Molecular Biology · doi:10.1016/j.jmb.2025.169125 · Cited by 12
“42,43 We tested the influence of the MoRF-1 region on the Drp1 lattice.”
Evolution of A bHLH Interaction Motif
Millard, P. S., Kragelund, B. B., & Burow, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22010447 · Cited by 10
Structural properties of the HNF-1A transactivation domain
Kind, L., Driver, M., Raasakka, A., Onck, P. R., Njølstad, P. R., Arnesen, T., & Kursula, P. (2023) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2023.1249939 · Cited by 10
“IDRs frequently harbor SLiMs, which are sequence elements of 6 - 12 residues that mediate the binding to folded interaction partners or promote LLPS by partaking in multivalent interactions (64).”
Background
The role of intrinsically disordered regions of SARS-CoV-2 nucleocapsid and non-structural protein 1 proteins
Shitaye, G., Ventserova, N., D’Abrosca, G., Dragone, M., Maina, E. W., Fattorusso, R., Iacovino, R., Russo, L., Isernia, C., & Malgieri, G. (2025) · Frontiers in Chemistry · doi:10.3389/fchem.2025.1597656 · Cited by 10
Disorder in a two-domain neuronal Ca2+-binding protein regulates domain stability and dynamics using ligand mimicry
Staby, L., Kemplen, K. R., Stein, A., Ploug, M., Clarke, J., Skriver, K., Heidarsson, P. O., & Kragelund, B. B. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03639-z · Cited by 10
Hidden Multivalency in Phosphatase Recruitment by a Disordered AKAP Scaffold
Watson, M. L., Almeida, T., Ray, A., Hanack, C., Elston, R., Btesh, J., McNaughton, P. A., & Stott, K. M. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167682 · Cited by 10
Disordered Domain Shifts the Conformational Ensemble of the Folded Regulatory Domain of the Multidomain Oncoprotein c-Src
Gurumoorthy, V., Shrestha, U. R., Zhang, Q., Pingali, S. V., Boder, E. T., Urban, V. S., Smith, J. C., Petridis, L., & O’Neill, H. (2023) · Biomacromolecules · doi:10.1021/acs.biomac.2c01158 · Cited by 10
Dissection of the role of a Src homology 3 domain in the evolution of binding preference of paralogous proteins
Lemieux, P., Bradley, D. T. C., Dubé, A. K., Dionne, U., & Landry, C. R. (2023) · Genetics · doi:10.1093/genetics/iyad175 · Cited by 8
“Furthermore, the mechanisms behind the contribution of disordered regions to PPI are also undefined, but the modifications of these regions, as we did by replacing the binding motif, can also affect binding in unexpected ways (Bugge et al. 2020).”
Background
Stm1 regulates Ifh1 activity revealing crosstalk between ribosome biogenesis and ribosome dormancy
Bianco, E., Bonassera, M., Uliana, F., Tilma, J., Winkler, M., Zencir, S., Gossert, A. D., Oborská‐Oplová, M., Dechant, R. C., Hugener, J., et al. (2025) · Molecular Cell · doi:10.1016/j.molcel.2025.04.008 · Cited by 10
Structure, dynamics, and stability of the globular domain of human linker histone H1 .0 and the role of positive charges
Martinsen, J. H., Saar, D., Fernandes, C. B., Schuler, B., Bugge, K., & Kragelund, B. B. (2022) · Protein Science · doi:10.1002/pro.4281 · Cited by 10
“The function and native conformation of protein domains are often effected by their full-chain context, 37 – 39 and accumulating evidence suggests that the binding mode of the GD in the nucleosome is influenced by its disordered tails.”
Background
Biophysical and Integrative Characterization of Protein Intrinsic Disorder as a Prime Target for Drug Discovery
Luo, S., Wohl, S., Zheng, W., & Yang, S. (2023) · Biomolecules · doi:10.3390/biom13030530 · Cited by 10
Conservation of Affinity Rather Than Sequence Underlies a Dynamic Evolution of the Motif-Mediated p53/MDM2 Interaction in Ray-Finned Fishes
Mihalič, F., Arcila, D., Pettersson, M. E., Farkhondehkish, P., Andersson, E., Andersson, L., Betancur‐R, R., & Jemth, P. (2024) · Molecular Biology and Evolution · doi:10.1093/molbev/msae018 · Cited by 8
“However, recent data suggested that flanking disordered regions of the binding motif may modulate affinity (Bugge et al. 2020; Theisen et al. 2021; Karlsson et al. 2022).”
Background
Metabotropic Glutamate Receptors at Ribbon Synapses in the Retina and Cochlea
Klotz, L., & Enz, R. (2022) · Cells · doi:10.3390/cells11071097 · Cited by 9
Biallelic variants in SNUPN cause a limb girdle muscular dystrophy with myofibrillar-like features
Iruzubieta, P., Damborenea, A., Ioghen, M. R., Bajew, S., Fernández‐Torrón, R., Töpf, A., Herrero-Reiriz, Á., Epure, D., Vill, K., Hernández‐Laín, A., et al. (2024) · Brain · doi:10.1093/brain/awae046 · Cited by 8
“15 Specifically, the IDR may act as a swinging arm 57 that permits high amplitude motions required for binding or as a flanking region 58 to the folded domains.”
Background
The Participation of the Intrinsically Disordered Regions of the bHLH-PAS Transcription Factors in Disease Development
Kolonko, M., Uversky, V. N., & Greb‐Markiewicz, B. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22062868 · Cited by 9
“Interestingly, protein-protein interaction (PPI) could lead to LLPS formation, which enable the partition of specific functions, but in contrast LLPS may also prevent from protein interactions [22,23][24].”
Background
Disordered proteins mitigate the temperature dependence of site-specific binding free energies
Thole, J. F., Waudby, C. A., & Pielak, G. J. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.102984 · Cited by 9
Intrinsically Disordered Flanking Regions Increase the Affinity of a Transcriptional Coactivator Interaction across Vertebrates
Karlsson, E., Ottoson, C., Ye, W., Andersson, E., & Jemth, P. (2023) · Biochemistry · doi:10.1021/acs.biochem.3c00285 · Cited by 8
Engineering intrinsically disordered regions for guiding genome navigation
Liu, J., Kumar, D. K., Hurieva, B., Jonas, F., & Barkai, N. (2026) · Molecular Cell · doi:10.1016/j.molcel.2026.01.019 · Cited by 9

Authors: Bugge, K., Brakti, I., Fernandes, C. B., Dreier, J. E., Lundsgaard, J. E., Olsen, J. G., Skriver, K., & Kragelund, B. B.
Affiliations: University of Copenhagen (DK)
Corresponding author: Skriver, Karen
Kragelund, Birthe B.
ORCID: Bugge, Katrine
Brakti, Inna
Fernandes, Catarina B.
Dreier, Jesper E.
Olsen, Johan G.
Skriver, Karen
Kragelund, Birthe B.
Venue: Frontiers in Molecular Biosciences
Publisher: Frontiers Media SA
Published: 2020-06-16
Volume: 7
Pages: 110-110
ISSN: 2296-889X (ISSN-L)
DOI: 10.3389/fmolb.2020.00110
PMC: PMC7308724
OpenAlex: W3036355682
Cited by: 155
References: 159
Citations by year: 2026: 16 · 2025: 21 · 2024: 20 · 2023: 31 · 2022: 34 · 2021: 24 · 2020: 9
FWCI: 2.35
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Frontiers in Molecular Biosciences (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: Novo Nordisk Fonden
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 14-3-3 protein interactions
Keywords: protein-protein interaction, intrinsically disordered proteins, structural disorder, flanking regions, context-dependent interactions, short linear motifs, multivalency, charge clusters, hydrophobic patch, allosteric regulation, feedback regulation, protein-protein interaction network, drug discovery

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Interactions by Disorder – A Matter of Context

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