Heterodimers of photoreceptor-specific nuclear receptor (PNR/NR2E3) and peroxisome proliferator-activated receptor (PPARγ) are disrupted by retinal disease-associated mutations
Photoreceptor-specific nuclear receptor (PNR/NR2E3) and Tailless homolog (TLX/NR2E1) are human orthologs of the NR2E group, a subgroup of phylogenetically related members of the Nuclear Receptor (NR) superfamily of transcription factors. We assessed the ability of these NRs to form heterodimers with...
| Main Authors: | , , , , , , , , , , , , , , |
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Nature Publishing Group
2017
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| Online Access: | https://eprints.nottingham.ac.uk/40567/ |
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| author | Fulton, Joel Mazumder, Bismoy Whitchurch, Jonathan Monteiro, Cintia J. Collins, Hilary M. Chan, Chun M. Clemente, Maria P. Hernandez Quiles, Miguel Stewart, Elizabeth A. Amoaku, Winfried Moran, Paula M. Mongan, Nigel P. Persson, Jenny L. Ali, Simak Heery, David M. |
| author_facet | Fulton, Joel Mazumder, Bismoy Whitchurch, Jonathan Monteiro, Cintia J. Collins, Hilary M. Chan, Chun M. Clemente, Maria P. Hernandez Quiles, Miguel Stewart, Elizabeth A. Amoaku, Winfried Moran, Paula M. Mongan, Nigel P. Persson, Jenny L. Ali, Simak Heery, David M. |
| author_sort | Fulton, Joel |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Photoreceptor-specific nuclear receptor (PNR/NR2E3) and Tailless homolog (TLX/NR2E1) are human orthologs of the NR2E group, a subgroup of phylogenetically related members of the Nuclear Receptor (NR) superfamily of transcription factors. We assessed the ability of these NRs to form heterodimers with other members of the human NRs representing all major subgroups. The TLX ligand binding domain (LBD) did not appear to form homodimers or interact directly with any other NR tested. The PNR LBD was able to form homodimers, but also exhibited robust interactions with the LBDs of PPARγ/NR1C3 and TRβ/NR1A2. The binding of PNR to PPARγ was specific for this paralog, as no interaction was observed with the LBDs of PPARαNR1C1 or PPARδNR1C2. In support of these findings, PPARγ and PNR were found to be co-expressed in human retinal tissue extracts and could be co-immunoprecipitated as a native complex. Selected sequence variants in the PNR LBD associated with human retinopathies, or a mutation in the dimerization region of PPARγ LBD associated with familial partial lipodystrophy type 3, were found to disrupt PNR/PPARγ complex formation. Wild type PNR, but not a PNR309G mutant, was able to repress PPARγ-mediated transcription in reporter assays. In summary our results reveal novel heterodimer interactions in the NR superfamily, suggesting previously unknown functional interactions of PNR with PPARγ and TRβ that have potential importance in retinal development and disease. |
| first_indexed | 2025-11-14T19:42:25Z |
| format | Article |
| id | nottingham-40567 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:42:25Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-405672020-05-04T18:38:05Z https://eprints.nottingham.ac.uk/40567/ Heterodimers of photoreceptor-specific nuclear receptor (PNR/NR2E3) and peroxisome proliferator-activated receptor (PPARγ) are disrupted by retinal disease-associated mutations Fulton, Joel Mazumder, Bismoy Whitchurch, Jonathan Monteiro, Cintia J. Collins, Hilary M. Chan, Chun M. Clemente, Maria P. Hernandez Quiles, Miguel Stewart, Elizabeth A. Amoaku, Winfried Moran, Paula M. Mongan, Nigel P. Persson, Jenny L. Ali, Simak Heery, David M. Photoreceptor-specific nuclear receptor (PNR/NR2E3) and Tailless homolog (TLX/NR2E1) are human orthologs of the NR2E group, a subgroup of phylogenetically related members of the Nuclear Receptor (NR) superfamily of transcription factors. We assessed the ability of these NRs to form heterodimers with other members of the human NRs representing all major subgroups. The TLX ligand binding domain (LBD) did not appear to form homodimers or interact directly with any other NR tested. The PNR LBD was able to form homodimers, but also exhibited robust interactions with the LBDs of PPARγ/NR1C3 and TRβ/NR1A2. The binding of PNR to PPARγ was specific for this paralog, as no interaction was observed with the LBDs of PPARαNR1C1 or PPARδNR1C2. In support of these findings, PPARγ and PNR were found to be co-expressed in human retinal tissue extracts and could be co-immunoprecipitated as a native complex. Selected sequence variants in the PNR LBD associated with human retinopathies, or a mutation in the dimerization region of PPARγ LBD associated with familial partial lipodystrophy type 3, were found to disrupt PNR/PPARγ complex formation. Wild type PNR, but not a PNR309G mutant, was able to repress PPARγ-mediated transcription in reporter assays. In summary our results reveal novel heterodimer interactions in the NR superfamily, suggesting previously unknown functional interactions of PNR with PPARγ and TRβ that have potential importance in retinal development and disease. Nature Publishing Group 2017-03-16 Article PeerReviewed Fulton, Joel, Mazumder, Bismoy, Whitchurch, Jonathan, Monteiro, Cintia J., Collins, Hilary M., Chan, Chun M., Clemente, Maria P., Hernandez Quiles, Miguel, Stewart, Elizabeth A., Amoaku, Winfried, Moran, Paula M., Mongan, Nigel P., Persson, Jenny L., Ali, Simak and Heery, David M. (2017) Heterodimers of photoreceptor-specific nuclear receptor (PNR/NR2E3) and peroxisome proliferator-activated receptor (PPARγ) are disrupted by retinal disease-associated mutations. Cell Death and Disease, 8 . e2677/1-e2677/11. ISSN 2041-4889 nuclear receptor NR2E3 NR2E1 NR1C3 photoreceptor specific nuclear receptor (PNR) Tailless (TLX) peroxisome proliferator activated receptor (PPAR) dimerization protein protein interaction enhanced S-cone syndrome http://www.nature.com/cddis/journal/v8/n3/full/cddis201798a.html doi:10.1038/cddis.2017.98 doi:10.1038/cddis.2017.98 |
| spellingShingle | nuclear receptor NR2E3 NR2E1 NR1C3 photoreceptor specific nuclear receptor (PNR) Tailless (TLX) peroxisome proliferator activated receptor (PPAR) dimerization protein protein interaction enhanced S-cone syndrome Fulton, Joel Mazumder, Bismoy Whitchurch, Jonathan Monteiro, Cintia J. Collins, Hilary M. Chan, Chun M. Clemente, Maria P. Hernandez Quiles, Miguel Stewart, Elizabeth A. Amoaku, Winfried Moran, Paula M. Mongan, Nigel P. Persson, Jenny L. Ali, Simak Heery, David M. Heterodimers of photoreceptor-specific nuclear receptor (PNR/NR2E3) and peroxisome proliferator-activated receptor (PPARγ) are disrupted by retinal disease-associated mutations |
| title | Heterodimers of photoreceptor-specific nuclear receptor (PNR/NR2E3) and peroxisome proliferator-activated receptor (PPARγ) are disrupted by retinal disease-associated mutations |
| title_full | Heterodimers of photoreceptor-specific nuclear receptor (PNR/NR2E3) and peroxisome proliferator-activated receptor (PPARγ) are disrupted by retinal disease-associated mutations |
| title_fullStr | Heterodimers of photoreceptor-specific nuclear receptor (PNR/NR2E3) and peroxisome proliferator-activated receptor (PPARγ) are disrupted by retinal disease-associated mutations |
| title_full_unstemmed | Heterodimers of photoreceptor-specific nuclear receptor (PNR/NR2E3) and peroxisome proliferator-activated receptor (PPARγ) are disrupted by retinal disease-associated mutations |
| title_short | Heterodimers of photoreceptor-specific nuclear receptor (PNR/NR2E3) and peroxisome proliferator-activated receptor (PPARγ) are disrupted by retinal disease-associated mutations |
| title_sort | heterodimers of photoreceptor-specific nuclear receptor (pnr/nr2e3) and peroxisome proliferator-activated receptor (pparγ) are disrupted by retinal disease-associated mutations |
| topic | nuclear receptor NR2E3 NR2E1 NR1C3 photoreceptor specific nuclear receptor (PNR) Tailless (TLX) peroxisome proliferator activated receptor (PPAR) dimerization protein protein interaction enhanced S-cone syndrome |
| url | https://eprints.nottingham.ac.uk/40567/ https://eprints.nottingham.ac.uk/40567/ https://eprints.nottingham.ac.uk/40567/ |