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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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Crossref · 10.3389/fmolb.2020.00110

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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.
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).
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.
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).
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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Metadata

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
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
Licence
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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