Structural Insights into the Interaction of the Intrinsically Disordered Co-activator TIF2 with Retinoic Acid Receptor Heterodimer (RXR/RAR)

Senicourt, Lucile; Maire, Albane le; Allemand, Frédéric; Carvalho, João E.; Guée, Laura; Germain, Pierre; Schubert, Michael; Bernadó, Pau; Bourguet, William; Sibille, Nathalie

doi:10.1016/j.jmb.2021.166899

Cited by 15 publications

(18 citation statements)

References 131 publications

(183 reference statements)

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“…3, upper panel). More specifically, the structure shows that the C-terminal extension of the LxxLL motif folds as a long α-helix making hydrophobic contacts with residues from both the LxxLL helix and RAR helices H3 and H12, thereby inducing a three-fold increase of the affinity of the LxxLL motif for RAR but not for RXR [41]. In contrast to full agonists, partial agonists incompletely stabilize the active form of the receptor (Fig.…”

Section: Structural Basis Of Ligand-regulated Co-regulators Interaction and Exchangementioning

confidence: 99%

“…Some studies argued in favor of the deck model where each subunit interacts with one coregulatory binding motif [36,46,48], while other studies reported an asymmetric model where RAR is the unique contributor to the interaction with co-regulators [45]. Two recent studies combining of a large set of biophysical and computational methods allowed to somehow reconcile these seemingly conflicting views by demonstrating that NRIDs form highly dynamic complexes with RAR-RXR, with singly and doubly bound species, and that the equilibrium can be modulated by ligands and mutations [41,49]. Moreover, they revealed that while the NRID of corepressors and coactivators is mainly disordered, it presents transient but robust intramolecular contacts upon interaction with the heterodimer, indicating that disorder-to-order transitions are key events in the regulation of NR heterodimers.…”

Section: Lessons From Structural Studiesmentioning

confidence: 99%

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Ligands and DNA in the allosteric control of retinoid receptors function

Germain

Rochel

Bourguet

2021

Essays in Biochemistry

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Retinoids are a family of compounds that include both vitamin A (all-trans retinol) and its naturally occurring metabolites such as retinoic acids (e.g. all-trans retinoic acid) as well as synthetic analogs. They are critically involved in the regulation of a wide variety of essential biological processes, such as embryogenesis and organogenesis, apoptosis, reproduction, vision, and the growth and differentiation of normal and neoplastic cells in vertebrates. The ability of these small molecules to control the expression of several hundred genes through binding to nuclear ligand-dependent transcription factors accounts for most of their functions. Three retinoic acid receptor (RARα,β,γ) and three retinoid X receptor (RXRα,β,γ) subtypes form a variety of RXR–RAR heterodimers that have been shown to mediate the pleiotropic effects of retinoids through the recruitment of high-molecular weight co-regulatory complexes to response-element DNA sequences found in the promoter region of their target genes. Hence, heterodimeric retinoid receptors are multidomain entities that respond to various incoming signals, such as ligand and DNA binding, by allosteric structural alterations which are the basis of further signal propagation. Here, we provide an overview of the current state of knowledge with regard to the structural mechanisms by which retinoids and DNA response elements act as allosteric effectors that may combine to finely tune RXR–RAR heterodimers activity.

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Section: Structural Basis Of Ligand-regulated Co-regulators Interaction and Exchangementioning

confidence: 99%

Section: Lessons From Structural Studiesmentioning

confidence: 99%

Ligands and DNA in the allosteric control of retinoid receptors function

Germain

Rochel

Bourguet

2021

Essays in Biochemistry

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“…By comparing the averaged SAXS profiles computed from both ensembles with the experimental one, the relative populations of the two binding modes in the apo form and in the presence of NR ligands were determined [136] . For the case of co-activators, no detailed model of the complexes has been proposed, although the presence of simultaneous binding has been demonstrated [137] , [138] , [139] . Interestingly, for TIF2 NRID co-activator, NMR experiments highlighted the involvement of TIF2 NRID NR-box2 flanking region in its interaction with RXR/RAR heterodimer.…”

Section: Interactions Between Disordered Regions and Structured Domainsmentioning

confidence: 99%

“…Interestingly, for TIF2 NRID co-activator, NMR experiments highlighted the involvement of TIF2 NRID NR-box2 flanking region in its interaction with RXR/RAR heterodimer. The specific fragment encompassing NR-box2 and its flanking ordered region was co-crystalized with RAR bound to an agonist, and revealed an interacting helix turn helix motif of the TIF2 NRID fragment on the RAR surface [139] . The exact role of this flanking region in the recognition mechanism and the effects on the overall arrangement of the complex remain to be deciphered.…”

Section: Interactions Between Disordered Regions and Structured Domainsmentioning

confidence: 99%

The diversity of molecular interactions involving intrinsically disordered proteins: A molecular modeling perspective

Clerc

Sagar

Barducci

et al. 2021

Computational and Structural Biotechnology Journal

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Intrinsically Disordered Proteins and Regions (IDPs/IDRs) are key components of a multitude of biological processes. Conformational malleability enables IDPs/IDRs to perform very specialized functions that cannot be accomplished by globular proteins. The functional role for most of these proteins is related to the recognition of other biomolecules to regulate biological processes or as a part of signaling pathways. Depending on the extent of disorder, the number of interacting sites and the type of partner, very different architectures for the resulting assemblies are possible. More recently, molecular condensates with liquid-like properties composed of multiple copies of IDPs and nucleic acids have been proven to regulate key processes in eukaryotic cells. The structural and kinetic details of disordered biomolecular complexes are difficult to unveil experimentally due to their inherent conformational heterogeneity. Computational approaches, alone or in combination with experimental data, have emerged as unavoidable tools to understand the functional mechanisms of this elusive type of assemblies. The level of description used, all-atom or coarse-grained, strongly depends on the size of the molecular systems and on the timescale of the investigated mechanism. In this mini-review, we describe the most relevant architectures found for molecular interactions involving IDPs/IDRs and the computational strategies applied for their investigation.

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“…Structure pools can also be obtained from suitably parametrized MD simulations [16]. In practice, adjustment of the conformational search space to sample structures with predefined local conformational preferences is often desirable to obtain ensembles with good correspondence to experimental data [17].…”

Section: Introduction 1ensemble-based Modeling Of Protein Internal Dynamicsmentioning

confidence: 99%

DIPEND: An Open-Source Pipeline to Generate Ensembles of Disordered Segments Using Neighbor-Dependent Backbone Preferences

2021

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Ensemble-based structural modeling of flexible protein segments such as intrinsically disordered regions is a complex task often solved by selection of conformers from an initial pool based on their conformity to experimental data. However, the properties of the conformational pool are crucial, as the sampling of the conformational space should be sufficient and, in the optimal case, relatively uniform. In other words, the ideal sampling is both efficient and exhaustive. To achieve this, specialized tools are usually necessary, which might not be maintained in the long term, available on all platforms or flexible enough to be tweaked to individual needs. Here, we present an open-source and extendable pipeline to generate initial protein structure pools for use with selection-based tools to obtain ensemble models of flexible protein segments. Our method is implemented in Python and uses ChimeraX, Scwrl4, Gromacs and neighbor-dependent backbone distributions compiled and published previously by the Dunbrack lab. All these tools and data are publicly available and maintained. Our basic premise is that by using residue-specific, neighbor-dependent Ramachandran distributions, we can enhance the efficient exploration of the relevant region of the conformational space. We have also provided a straightforward way to bias the sampling towards specific conformations for selected residues by combining different conformational distributions. This allows the consideration of a priori known conformational preferences such as in the case of preformed structural elements. The open-source and modular nature of the pipeline allows easy adaptation for specific problems. We tested the pipeline on an intrinsically disordered segment of the protein Cd3ϵ and also a single-alpha helical (SAH) region by generating conformational pools and selecting ensembles matching experimental data using the CoNSEnsX+ server.

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Structural Insights into the Interaction of the Intrinsically Disordered Co-activator TIF2 with Retinoic Acid Receptor Heterodimer (RXR/RAR)

Cited by 15 publications

References 131 publications

Ligands and DNA in the allosteric control of retinoid receptors function

Ligands and DNA in the allosteric control of retinoid receptors function

The diversity of molecular interactions involving intrinsically disordered proteins: A molecular modeling perspective

DIPEND: An Open-Source Pipeline to Generate Ensembles of Disordered Segments Using Neighbor-Dependent Backbone Preferences

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