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Cross-Talk between PPARs and the Partners of RXR: A Molecular Perspective.

Chan LS, Wells RA - PPAR Res (2009)

Bottom Line: As a result, many heterodimers share the same DR element and must complete with each other for DNA binding.As a result, individual nuclear receptors must complete with each other for RXR to form functional heterodimers.These tools will enable future studies to dissect specific RXR heterodimers and their signaling pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 2M9.

ABSTRACT
The PPARs are integral parts of the RXR-dependent signaling networks. Many other nuclear receptor subfamily 1 members also require RXR as their obligatory heterodimerization partner and they are often co-expressed in any given tissue. Therefore, the PPARs often complete with other RXR-dependent nuclear receptors and this competition has important biological implications. Thorough understanding of this cross-talk at the molecular level is crucial to determine the detailed functional roles of the PPARs. At the level of DNA binding, most RXR heterodimers bind selectively to the well-known "DR1 to 5" DNA response elements. As a result, many heterodimers share the same DR element and must complete with each other for DNA binding. At the level of heterodimerization, the partners of RXR share the same RXR dimerization interface. As a result, individual nuclear receptors must complete with each other for RXR to form functional heterodimers. Cross-talk through DNA binding and RXR heterodimerization present challenges to the study of these nuclear receptors that cannot be adequately addressed by current experimental approaches. Novel tools, such as engineered nuclear receptors with altered dimerization properties, are currently being developed. These tools will enable future studies to dissect specific RXR heterodimers and their signaling pathways.

No MeSH data available.


Related in: MedlinePlus

(a) Ribbon drawing of the human RXRα/human PPARγ heterodimer on PPRE (PBD 3E00). (b) Ribbon drawing of the heterodimer/DNA complex showing only the PPRE and the DBDs of RXRα and PPARγ. The RXR and PPAR monomers are colored in dark and light grey, respectively. The PPRE is colored in black; the 5′ and 3′ ends are also labeled.
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fig1: (a) Ribbon drawing of the human RXRα/human PPARγ heterodimer on PPRE (PBD 3E00). (b) Ribbon drawing of the heterodimer/DNA complex showing only the PPRE and the DBDs of RXRα and PPARγ. The RXR and PPAR monomers are colored in dark and light grey, respectively. The PPRE is colored in black; the 5′ and 3′ ends are also labeled.

Mentions: Most RXR/partner heterodimers recognize and bind to direct repeat (DR) DNA sequences as their response element [18–23]. The consensus DR sequence consists of two direct repeat half-sites separated by a number of nucleotides (5′-AGGTCA n(x) AGGTCA-3′). A DR separated by a single nucleotide is referred to as DNA response element direct repeat 1 (DR1). In addition, the sequence of the actual 5′-AGGTCA-3′ half-site varies among different response elements. The RXRα/PPARγ heterodimer preferentially binds to the DR1 PPAR response element (PPRE) [24], and the crystal structure of this heterodimer/DNA complex is recently reported (Figure 1) [25]. During DNA binding, the heterodimer is arranged such that the DNA binding domain (DBD) from each monomer occupies one 5′-AGGTCA-3′ half-site. Most heterodimers are selective toward DR sequences with one to five nucleotides spacing (i.e., DR1 to DR5). At the molecular level, addition or subtraction of a single base pair between the half-sites imposes a separation of 3.4 Å and a rotation of 36° between the two half-sites [19]. Since a DBD is only slightly longer than one half-site, the structural conformations required for the heterodimers vary greatly for different DRs. Heterodimerization of the DBDs on their correct DR elements helps define the structural conformation of the heterodimer, which in turn stabilizes the protein/DNA complex. It is also worth noting that the RXR DBD is flexible and undergoes structural changes to accommodate the DBDs from different partners.


Cross-Talk between PPARs and the Partners of RXR: A Molecular Perspective.

Chan LS, Wells RA - PPAR Res (2009)

(a) Ribbon drawing of the human RXRα/human PPARγ heterodimer on PPRE (PBD 3E00). (b) Ribbon drawing of the heterodimer/DNA complex showing only the PPRE and the DBDs of RXRα and PPARγ. The RXR and PPAR monomers are colored in dark and light grey, respectively. The PPRE is colored in black; the 5′ and 3′ ends are also labeled.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2801013&req=5

fig1: (a) Ribbon drawing of the human RXRα/human PPARγ heterodimer on PPRE (PBD 3E00). (b) Ribbon drawing of the heterodimer/DNA complex showing only the PPRE and the DBDs of RXRα and PPARγ. The RXR and PPAR monomers are colored in dark and light grey, respectively. The PPRE is colored in black; the 5′ and 3′ ends are also labeled.
Mentions: Most RXR/partner heterodimers recognize and bind to direct repeat (DR) DNA sequences as their response element [18–23]. The consensus DR sequence consists of two direct repeat half-sites separated by a number of nucleotides (5′-AGGTCA n(x) AGGTCA-3′). A DR separated by a single nucleotide is referred to as DNA response element direct repeat 1 (DR1). In addition, the sequence of the actual 5′-AGGTCA-3′ half-site varies among different response elements. The RXRα/PPARγ heterodimer preferentially binds to the DR1 PPAR response element (PPRE) [24], and the crystal structure of this heterodimer/DNA complex is recently reported (Figure 1) [25]. During DNA binding, the heterodimer is arranged such that the DNA binding domain (DBD) from each monomer occupies one 5′-AGGTCA-3′ half-site. Most heterodimers are selective toward DR sequences with one to five nucleotides spacing (i.e., DR1 to DR5). At the molecular level, addition or subtraction of a single base pair between the half-sites imposes a separation of 3.4 Å and a rotation of 36° between the two half-sites [19]. Since a DBD is only slightly longer than one half-site, the structural conformations required for the heterodimers vary greatly for different DRs. Heterodimerization of the DBDs on their correct DR elements helps define the structural conformation of the heterodimer, which in turn stabilizes the protein/DNA complex. It is also worth noting that the RXR DBD is flexible and undergoes structural changes to accommodate the DBDs from different partners.

Bottom Line: As a result, many heterodimers share the same DR element and must complete with each other for DNA binding.As a result, individual nuclear receptors must complete with each other for RXR to form functional heterodimers.These tools will enable future studies to dissect specific RXR heterodimers and their signaling pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 2M9.

ABSTRACT
The PPARs are integral parts of the RXR-dependent signaling networks. Many other nuclear receptor subfamily 1 members also require RXR as their obligatory heterodimerization partner and they are often co-expressed in any given tissue. Therefore, the PPARs often complete with other RXR-dependent nuclear receptors and this competition has important biological implications. Thorough understanding of this cross-talk at the molecular level is crucial to determine the detailed functional roles of the PPARs. At the level of DNA binding, most RXR heterodimers bind selectively to the well-known "DR1 to 5" DNA response elements. As a result, many heterodimers share the same DR element and must complete with each other for DNA binding. At the level of heterodimerization, the partners of RXR share the same RXR dimerization interface. As a result, individual nuclear receptors must complete with each other for RXR to form functional heterodimers. Cross-talk through DNA binding and RXR heterodimerization present challenges to the study of these nuclear receptors that cannot be adequately addressed by current experimental approaches. Novel tools, such as engineered nuclear receptors with altered dimerization properties, are currently being developed. These tools will enable future studies to dissect specific RXR heterodimers and their signaling pathways.

No MeSH data available.


Related in: MedlinePlus