High affinity between <scp>CREBBP</scp>/p300 and <scp>NCOA</scp> evolved in vertebrates

Karlsson, Elin; Lindberg, Amanda; Andersson, Eva; Jemth, Per

doi:10.1002/pro.3868

Cited by 9 publications

(16 citation statements)

References 12 publications

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“…Firstly, while it has a hydrophobic core and globular shape, NCBD is a very dynamic protein domain with characteristics of an IDP 3,6-9,22,24 . Secondly, NCBD has several binding partners including the three NCOA transcriptional co-regulator paralogs 3,25 , the transcription factors p53 26 , Ets-2 of the complex between CID and NCBD suggest that several new intermolecular contacts and conformational plasticity increased the affinity when going from the Cambrian-like NCBDD/P ML (Kd ~ 1-5 µM) to younger variants (Kd ~ 0.2 µM) 10,11,31 .…”

Section: Discussionmentioning

confidence: 99%

“…Intriguingly, NCBD displays great conformational plasticity as shown by its complex with interferon factor-3 where the helices of NCBD adopt a distinct conformation as compared to the complex with CID ( 31 ). Thirdly, evolutionary snapshots of the complex between CID and NCBD suggest that several new intermolecular contacts and conformational plasticity increased the affinity when going from the Cambrian-like NCBD D/P ML ( K d ~ 1-5 μM) to younger variants ( K d ~ 0.2 μM) ( 12, 13, 32 ). Fourthly, while affinity and structural order of modern NCBD/CID complexes were increased, the transition state of the folding-induced binding displayed more conformational heterogeneity as compared to the ancestral complex ( 33 ).…”

Section: Discussionmentioning

confidence: 99%

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The dynamic properties of a nuclear coactivator binding domain are evolutionarily conserved

Karlsson

Andersson

et al. 2021

Preprint

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Evolution of proteins is constrained by their structure and function. While there is a consensus that the plasticity of intrinsically disordered proteins relaxes the structural constraints on evolution there is a paucity of data on the molecular details of these processes. The Nuclear co-activator binding domain (NCBD) from CREB-binding protein is a protein-protein interaction domain, which contains a hydrophobic core but is verging on being intrinsically disordered. These highly dynamic 'borderline' properties of NCBD makes it an interesting model system for evolutionary structure-function investigation. We have here compared the structure and biophysical properties of an ancient version of NCBD present in a bilaterian animal ancestor living around 600 million years ago with extant human NCBD. Using a combination of NMR spectroscopy, circular dichroism and kinetic methods we show that NCBD has retained its structure and dynamic biophysical properties in the ligand-free state in the evolutionary lineage leading from the bilaterian ancestor to humans. Our findings suggest that the dynamic properties of NCBD are subject to positive selection and thus important for its function, which includes mediating several distinct protein-protein interactions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The dynamic properties of a nuclear coactivator binding domain are evolutionarily conserved

Karlsson

Andersson

et al. 2021

Preprint

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“…Finally, the NCBD/CID affinity is relatively constant across the deuterostome animal kingdom ( Fig. 1 ) despite several differences in the primary structure ( 4 , 27 ), and it is therefore likely that the binding mechanism is also conserved.…”

Section: Discussionmentioning

confidence: 99%

“…CID likely emerged later as an interaction domain within the ancestral ACTR/TIF2/SRC protein in the deuterostome lineage (including chordates, echinoderms and hemichordates; Fig. 1) (4,27). The evolution of the NCBD/CID interaction was previously examined using ancestral sequence reconstruction in combination with several biophysical methods to assess differences in affinity, structure and dynamics between the extant and ancestral protein complex.…”

Section: Introductionmentioning

confidence: 99%

Mapping the transition state for a binding reaction between ancient intrinsically disordered proteins

Karlsson

Paissoni

Erkelens

et al. 2020

Journal of Biological Chemistry

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Intrinsically disordered protein domains often have multiple binding partners. It is plausible that the strength of pairing with specific partners evolves from an initial low to higher affinity. However, little is known about the molecular changes in the binding mechanism that would facilitate such a transition. We previously showed that the interaction between two intrinsically disordered domains, NCBD and CID, likely emerged in an ancestral deuterostome organism as a low-affinity interaction that subsequently evolved into a higher-affinity interaction before the radiation of modern vertebrate groups. Here we map native contacts in the transition states of the low-affinity ancestral and high-affinity human NCBD/CID interactions. We show that the coupled binding and folding mechanism is overall similar, but with a higher degree of native hydrophobic contact formation in the transition state of the ancestral complex and more heterogeneous transient interactions, including electrostatic pairings, and an increased disorder for the human complex. Adaptation to new binding partners may be facilitated by this ability to exploit multiple alternative transient interactions while retaining the overall binding and folding pathway.

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“…Thus, binding is complex, likely involving allovalency ( 142 ) targeting the same site and exploiting increased local concentration effects ( 143 ). For the CBP-NCBD:ACTR association, a positive effect on binding affinity of the NCBD domain context was also demonstrated ( 144 ), highlighting the intricate regulatory potential of context, also involving the αα-hubs. The additional binding site in CCM2-HHD (see above) is reflected in bound MEKK3, where the N-terminal α-helix targeting the CCM2-HHD supersite is followed by a PB1 domain, also contributing to binding ( 30 , 124 ).…”

Section: Mechanisms and Concepts Of αα-Hub Modus Operandi mentioning

confidence: 99%

αα-Hub domains and intrinsically disordered proteins: A decisive combo

Bugge

Staby

Salladini

et al. 2021

Journal of Biological Chemistry

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Hub proteins are central nodes in protein–protein interaction networks with critical importance to all living organisms. Recently, a new group of folded hub domains, the αα-hubs, was defined based on a shared αα-hairpin supersecondary structural foundation. The members PAH, RST, TAFH, NCBD, and HHD are found in large proteins such as Sin3, RCD1, TAF4, CBP, and harmonin, which organize disordered transcriptional regulators and membrane scaffolds in interactomes of importance to human diseases and plant quality. In this review, studies of structures, functions, and complexes across the αα-hubs are described and compared to provide a unified description of the group. This analysis expands the associated molecular concepts of “one domain–one binding site”, motif-based ligand binding, and coupled folding and binding of intrinsically disordered ligands to additional concepts of importance to signal fidelity. These include context, motif reversibility, multivalency, complex heterogeneity, synergistic αα-hub:ligand folding, accessory binding sites, and supramodules. We propose that these multifaceted protein–protein interaction properties are made possible by the characteristics of the αα-hub fold, including supersite properties, dynamics, variable topologies, accessory helices, and malleability and abetted by adaptability of the disordered ligands. Critically, these features provide additional filters for specificity. With the presentations of new concepts, this review opens for new research questions addressing properties across the group, which are driven from concepts discovered in studies of the individual members. Combined, the members of the αα-hubs are ideal models for deconvoluting signal fidelity maintained by folded hubs and their interactions with intrinsically disordered ligands.

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High affinity between CREBBP/p300 and NCOA evolved in vertebrates

Cited by 9 publications

References 12 publications

The dynamic properties of a nuclear coactivator binding domain are evolutionarily conserved

The dynamic properties of a nuclear coactivator binding domain are evolutionarily conserved

Mapping the transition state for a binding reaction between ancient intrinsically disordered proteins

αα-Hub domains and intrinsically disordered proteins: A decisive combo

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