RXR heterodimerization allosterically activates LXR binding to the second NR box of activating signal co-integrator-2

You Lee Son, Ok Gu Park, Gwang Sik Kim, Jae Lee, Young Chul Lee

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

ASC-2 (activating signal co-integrator-2) is a transcriptional co-activator that mediates the transactivation of NRs (nuclear receptors) via direct interactions with these receptors. ASC-2 contains two separate NR-interaction domains harbouring a core signature motif, LXXLL (where X is any amino acid), named the NR box. Although the first NR box (NR box-1) of ASC-2 interacts with many different NRs, the second NR box (NR box-2) specifically interacts with only LXR (liver X receptor), whose transactivation in vivo requires heterodimerization with RXR (retinoid X receptor). Interestingly, RXR has been shown to enhance the LXR transactivation, even in the absence of LXR ligand via a unique mechanism of allosteric regulation. In the present study we demonstrate that LXR binding to an ASC-2 fragment containing NR box-2 (Co4aN) is enhanced by RXR and even further by liganded RXR. We also identified specific residues in Co4aN involved in its interaction with LXR that were also required for the ASC-2-mediated transactivation of LXR in mammalian cells. Using these mutants, we found that the Co4aN-LXR interaction surface is not altered by the presence of RXR and RXR ligand and that the Ser1490 residue is the critical determinant for the LXR-specific interaction of Co4aN. Notably the NR box-2, but not the NR box-1, is essential for ASC-2-mediated transactivation of LXR in vivo and for the interaction between LXR-RXR and ASC-2 in vitro. These results indicate that RXR does not interact directly with NR box-1 of ASC-2, but functions as an allosteric activator of LXR binding to NR box-2 of ASC-2.

Original languageEnglish (US)
Pages (from-to)319-330
Number of pages12
JournalBiochemical Journal
Volume410
Issue number2
DOIs
StatePublished - Mar 1 2008
Externally publishedYes

Fingerprint

Retinoid X Receptors
Cytoplasmic and Nuclear Receptors
Liver
Transcriptional Activation
Liver X Receptors
Allosteric Regulation
Ligands

Keywords

  • Activating signal co-integrator 2 (ASC-2)
  • Interaction-defective mutants
  • Liver X receptor (LXR)
  • LXXLL motif
  • One- plus two-hybrid system
  • Phantom-ligand effect

ASJC Scopus subject areas

  • Biochemistry

Cite this

RXR heterodimerization allosterically activates LXR binding to the second NR box of activating signal co-integrator-2. / Son, You Lee; Park, Ok Gu; Kim, Gwang Sik; Lee, Jae; Lee, Young Chul.

In: Biochemical Journal, Vol. 410, No. 2, 01.03.2008, p. 319-330.

Research output: Contribution to journalArticle

Son, You Lee ; Park, Ok Gu ; Kim, Gwang Sik ; Lee, Jae ; Lee, Young Chul. / RXR heterodimerization allosterically activates LXR binding to the second NR box of activating signal co-integrator-2. In: Biochemical Journal. 2008 ; Vol. 410, No. 2. pp. 319-330.
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abstract = "ASC-2 (activating signal co-integrator-2) is a transcriptional co-activator that mediates the transactivation of NRs (nuclear receptors) via direct interactions with these receptors. ASC-2 contains two separate NR-interaction domains harbouring a core signature motif, LXXLL (where X is any amino acid), named the NR box. Although the first NR box (NR box-1) of ASC-2 interacts with many different NRs, the second NR box (NR box-2) specifically interacts with only LXR (liver X receptor), whose transactivation in vivo requires heterodimerization with RXR (retinoid X receptor). Interestingly, RXR has been shown to enhance the LXR transactivation, even in the absence of LXR ligand via a unique mechanism of allosteric regulation. In the present study we demonstrate that LXR binding to an ASC-2 fragment containing NR box-2 (Co4aN) is enhanced by RXR and even further by liganded RXR. We also identified specific residues in Co4aN involved in its interaction with LXR that were also required for the ASC-2-mediated transactivation of LXR in mammalian cells. Using these mutants, we found that the Co4aN-LXR interaction surface is not altered by the presence of RXR and RXR ligand and that the Ser1490 residue is the critical determinant for the LXR-specific interaction of Co4aN. Notably the NR box-2, but not the NR box-1, is essential for ASC-2-mediated transactivation of LXR in vivo and for the interaction between LXR-RXR and ASC-2 in vitro. These results indicate that RXR does not interact directly with NR box-1 of ASC-2, but functions as an allosteric activator of LXR binding to NR box-2 of ASC-2.",
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AU - Park, Ok Gu

AU - Kim, Gwang Sik

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AU - Lee, Young Chul

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