On the specificity of protein–protein interactions in the context of disorder

Teilum, Kaare; Olsen, Johan G.; Kragelund, Birthe B.

doi:10.1042/bcj20200828

Cited by 63 publications

(63 citation statements)

References 149 publications

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“…With the affinities in the 50-100 µM range uncovered in the present work, as well as in previous studies [42,44], it may very well be likely that calcium binding to IDPs may serve regulatory functional roles, which, however, remain to be uncovered. IDPs often engage in multivalent interactions [60], including those leading to liquid-liquid phase separation [61][62][63]. Emerging research shows that phase separation can be regulated by calcium in the endoplasmic/sarcoplasmic reticula to enable efficient calcium buffering [64].…”

Section: Discussionmentioning

confidence: 99%

Insight into Calcium-Binding Motifs of Intrinsically Disordered Proteins

et al. 2021

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Motifs within proteins help us categorize their functions. Intrinsically disordered proteins (IDPs) are rich in short linear motifs, conferring them many different roles. IDPs are also frequently highly charged and, therefore, likely to interact with ions. Canonical calcium-binding motifs, such as the EF-hand, often rely on the formation of stabilizing flanking helices, which are a key characteristic of folded proteins, but are absent in IDPs. In this study, we probe the existence of a calcium-binding motif relevant to IDPs. Upon screening several carefully selected IDPs using NMR spectroscopy supplemented with affinity quantification by colorimetric assays, we found calcium-binding motifs in IDPs which could be categorized into at least two groups—an Excalibur-like motif, sequentially similar to the EF-hand loop, and a condensed-charge motif carrying repetitive negative charges. The motifs show an affinity for calcium typically in the ~100 μM range relevant to regulatory functions and, while calcium binding to the condensed-charge motif had little effect on the overall compaction of the IDP chain, calcium binding to Excalibur-like motifs resulted in changes in compaction. Thus, calcium binding to IDPs may serve various structural and functional roles that have previously been underreported.

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Section: Discussionmentioning

confidence: 99%

Insight into Calcium-Binding Motifs of Intrinsically Disordered Proteins

et al. 2021

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“…The amino acid composition of the contact area of two interacting proteins (complex “A–B”) provides molecular recognition specificity [ 28 , 29 ]. Conventionally, it is possible to distinguish mono- or multispecific PPIs when the contact area of protein “A” interacts either strictly with protein “B” or other protein partners, respectively.…”

Section: Main Structural and Biochemical Features Of Ppis’ Interfacesmentioning

confidence: 99%

Interfacial Peptides as Affinity Modulating Agents of Protein-Protein Interactions

2022

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The identification of disease-related protein-protein interactions (PPIs) creates objective conditions for their pharmacological modulation. The contact area (interfaces) of the vast majority of PPIs has some features, such as geometrical and biochemical complementarities, “hot spots”, as well as an extremely low mutation rate that give us key knowledge to influence these PPIs. Exogenous regulation of PPIs is aimed at both inhibiting the assembly and/or destabilization of protein complexes. Often, the design of such modulators is associated with some specific problems in targeted delivery, cell penetration and proteolytic stability, as well as selective binding to cellular targets. Recent progress in interfacial peptide design has been achieved in solving all these difficulties and has provided a good efficiency in preclinical models (in vitro and in vivo). The most promising peptide-containing therapeutic formulations are under investigation in clinical trials. In this review, we update the current state-of-the-art in the field of interfacial peptides as potent modulators of a number of disease-related PPIs. Over the past years, the scientific interest has been focused on following clinically significant heterodimeric PPIs MDM2/p53, PD-1/PD-L1, HIF/HIF, NRF2/KEAP1, RbAp48/MTA1, HSP90/CDC37, BIRC5/CRM1, BIRC5/XIAP, YAP/TAZ–TEAD, TWEAK/FN14, Bcl-2/Bax, YY1/AKT, CD40/CD40L and MINT2/APP.

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“…These properties render them malleable and confer functional advantages, one of which is the ability to bind multiple binding partners. 11 , 12 Such binding often occurs by exploitation of minor, limited binding sites constituted by small linear motifs (SLiMs). 4 , 13 The prevalence of disordered proteins in the eukaryotic proteome 3 , 6 , 7 is evidence of their importance in biological processes, but due to their low sequence conservation compared to folded counterparts, 14 , 15 evolutionary links between different IDPs can be difficult to track and thus often relies on functional analyses.…”

Section: Introductionmentioning

confidence: 99%

The disordered PCI‐binding human proteins CSNAP and DSS1 have diverged in structure and function

et al. 2021

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Intrinsically disordered proteins (IDPs) regularly constitute components of larger protein assemblies contributing to architectural stability. Two small, highly acidic IDPs have been linked to the so-called PCI complexes carrying PCI-domain subunits, including the proteasome lid and the COP9 signalosome. These two IDPs, DSS1 and CSNAP, have been proposed to have similar structural propensities and functions, but they display differences in their interactions and interactome sizes. Here we characterized the structural properties of human DSS1 and CSNAP at the residue level using NMR spectroscopy and probed their propensities to bind ubiquitin. We find that distinct structural features present in DSS1 are completely absent in CSNAP, and vice versa, with lack of relevant ubiquitin binding to CSNAP, suggesting the two proteins to have diverged in both structure and function. Our work additionally highlights that different local features of seemingly similar IDPs, even subtle sequence variance, may endow them with different functional traits. Such traits may underlie their potential to engage in multiple interactions thereby impacting their interactome sizes.

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On the specificity of protein–protein interactions in the context of disorder

Cited by 63 publications

References 149 publications

Insight into Calcium-Binding Motifs of Intrinsically Disordered Proteins

Insight into Calcium-Binding Motifs of Intrinsically Disordered Proteins

Interfacial Peptides as Affinity Modulating Agents of Protein-Protein Interactions

The disordered PCI‐binding human proteins CSNAP and DSS1 have diverged in structure and function

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