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A structural signature motif enlightens the origin and diversification of nuclear receptors

Nuclear receptors are ligand-activated transcription factors that modulate gene regulatory networks from embryonic development to adult physiology and thus represent major targets for clinical interventions in many diseases. Most nuclear receptors function either as homodimers or as heterodimers. Th...

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Autores principales: Beinsteiner, Brice, Markov, Gabriel V., Erb, Stéphane, Chebaro, Yassmine, McEwen, Alastair G., Cianférani, Sarah, Laudet, Vincent, Moras, Dino, Billas, Isabelle M. L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092661/
https://www.ncbi.nlm.nih.gov/pubmed/33882063
http://dx.doi.org/10.1371/journal.pgen.1009492
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author Beinsteiner, Brice
Markov, Gabriel V.
Erb, Stéphane
Chebaro, Yassmine
McEwen, Alastair G.
Cianférani, Sarah
Laudet, Vincent
Moras, Dino
Billas, Isabelle M. L.
author_facet Beinsteiner, Brice
Markov, Gabriel V.
Erb, Stéphane
Chebaro, Yassmine
McEwen, Alastair G.
Cianférani, Sarah
Laudet, Vincent
Moras, Dino
Billas, Isabelle M. L.
author_sort Beinsteiner, Brice
collection PubMed
description Nuclear receptors are ligand-activated transcription factors that modulate gene regulatory networks from embryonic development to adult physiology and thus represent major targets for clinical interventions in many diseases. Most nuclear receptors function either as homodimers or as heterodimers. The dimerization is crucial for gene regulation by nuclear receptors, by extending the repertoire of binding sites in the promoters or the enhancers of target genes via combinatorial interactions. Here, we focused our attention on an unusual structural variation of the α-helix, called π-turn that is present in helix H7 of the ligand-binding domain of RXR and HNF4. By tracing back the complex evolutionary history of the π-turn, we demonstrate that it was present ancestrally and then independently lost in several nuclear receptor lineages. Importantly, the evolutionary history of the π-turn motif is parallel to the evolutionary diversification of the nuclear receptor dimerization ability from ancestral homodimers to derived heterodimers. We then carried out structural and biophysical analyses, in particular through point mutation studies of key RXR signature residues and showed that this motif plays a critical role in the network of interactions stabilizing homodimers. We further showed that the π-turn was instrumental in allowing a flexible heterodimeric interface of RXR in order to accommodate multiple interfaces with numerous partners and critical for the emergence of high affinity receptors. Altogether, our work allows to identify a functional role for the π-turn in oligomerization of nuclear receptors and reveals how this motif is linked to the emergence of a critical biological function. We conclude that the π-turn can be viewed as a structural exaptation that has contributed to enlarging the functional repertoire of nuclear receptors.
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spelling pubmed-80926612021-05-07 A structural signature motif enlightens the origin and diversification of nuclear receptors Beinsteiner, Brice Markov, Gabriel V. Erb, Stéphane Chebaro, Yassmine McEwen, Alastair G. Cianférani, Sarah Laudet, Vincent Moras, Dino Billas, Isabelle M. L. PLoS Genet Research Article Nuclear receptors are ligand-activated transcription factors that modulate gene regulatory networks from embryonic development to adult physiology and thus represent major targets for clinical interventions in many diseases. Most nuclear receptors function either as homodimers or as heterodimers. The dimerization is crucial for gene regulation by nuclear receptors, by extending the repertoire of binding sites in the promoters or the enhancers of target genes via combinatorial interactions. Here, we focused our attention on an unusual structural variation of the α-helix, called π-turn that is present in helix H7 of the ligand-binding domain of RXR and HNF4. By tracing back the complex evolutionary history of the π-turn, we demonstrate that it was present ancestrally and then independently lost in several nuclear receptor lineages. Importantly, the evolutionary history of the π-turn motif is parallel to the evolutionary diversification of the nuclear receptor dimerization ability from ancestral homodimers to derived heterodimers. We then carried out structural and biophysical analyses, in particular through point mutation studies of key RXR signature residues and showed that this motif plays a critical role in the network of interactions stabilizing homodimers. We further showed that the π-turn was instrumental in allowing a flexible heterodimeric interface of RXR in order to accommodate multiple interfaces with numerous partners and critical for the emergence of high affinity receptors. Altogether, our work allows to identify a functional role for the π-turn in oligomerization of nuclear receptors and reveals how this motif is linked to the emergence of a critical biological function. We conclude that the π-turn can be viewed as a structural exaptation that has contributed to enlarging the functional repertoire of nuclear receptors. Public Library of Science 2021-04-21 /pmc/articles/PMC8092661/ /pubmed/33882063 http://dx.doi.org/10.1371/journal.pgen.1009492 Text en © 2021 Beinsteiner et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Beinsteiner, Brice
Markov, Gabriel V.
Erb, Stéphane
Chebaro, Yassmine
McEwen, Alastair G.
Cianférani, Sarah
Laudet, Vincent
Moras, Dino
Billas, Isabelle M. L.
A structural signature motif enlightens the origin and diversification of nuclear receptors
title A structural signature motif enlightens the origin and diversification of nuclear receptors
title_full A structural signature motif enlightens the origin and diversification of nuclear receptors
title_fullStr A structural signature motif enlightens the origin and diversification of nuclear receptors
title_full_unstemmed A structural signature motif enlightens the origin and diversification of nuclear receptors
title_short A structural signature motif enlightens the origin and diversification of nuclear receptors
title_sort structural signature motif enlightens the origin and diversification of nuclear receptors
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092661/
https://www.ncbi.nlm.nih.gov/pubmed/33882063
http://dx.doi.org/10.1371/journal.pgen.1009492
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