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

• Brice, Beinsteiner

• Gabriel V., Markov

• Stéphane, Erb

• Yassmine, Chebaro

• Alastair G., McEwen

• Sarah, Cianférani

• Vincent, Laudet

• Dino, Moras

• Isabelle M. L., Billas

抄録

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 alpha-helix, called pi-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 pi-turn, we demonstrate that it was present ancestrally and then independently lost in several nuclear receptor lineages. Importantly, the evolutionary history of the pi-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 pi-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 pi-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 pi-turn can be viewed as a structural exaptation that has contributed to enlarging the functional repertoire of nuclear receptors.

source:https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1009492&rev=2

source:https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1009492&rev=1

収録刊行物

• PLOS Genetics

  PLOS Genetics 17 (4), e1009492-, 2021-04-21

  Public Library of Science

詳細情報

• CRID: 1050569690502173440
• NII論文ID: 120007038896
• ISSN: 15537404
• ISSN: 15537390
• Web Site: http://id.nii.ac.jp/1394/00001906/
• 本文言語コード: en
• 資料種別: journal article
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