Peroxisome Proliferator-Activated Receptors: Difference between revisions
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===Co-Activator & Co-Repressor Binding=== | ===Co-Activator & Co-Repressor Binding=== | ||
[[Image: SRC_binding.png| | [[Image: SRC_binding.png|250px|left| Human PPARγ Co-Activator Binding Site. PPARγ bound to SRC-1, [[3dzy]]]] | ||
The transcriptional activity of <scene name='Peroxisome_Proliferator-Activated_Receptors/Ppar_opening_2/2'>PPAR </scene>is regulated by its interaction with co-activators like SRC-1 or CBP and co-repressors like SMRT. <ref name="Zoete">PMID:17317294</ref>Co-activators like CBP contain a conserved LXXLL motif where X is any amino acid, and use this to bind a hydrophobic pocket on the receptor surface formed by the stabilized AF-2 helix H12.<ref name="Gampe">PMID:10882139</ref> In the case of the PPARγ/rosiglitazone/SRC-1 complex, the LXXLL motif helix of SRC-1 forms <scene name='Peroxisome_Proliferator-Activated_Receptors/Src_binding/1'>hydrophobic interactions with Leu468 and Leu318 of the LBD and hydrogen bonds between Glu471 and Lys301 and the co-activator backbone.</scene> These charged residues are conserved across PPAR isotypes and form the “charge clamp,” an essential component for co-activator stabilization in the PPAR LBD.<ref>PMID:11698662</ref> | The transcriptional activity of <scene name='Peroxisome_Proliferator-Activated_Receptors/Ppar_opening_2/2'>PPAR </scene>is regulated by its interaction with co-activators like SRC-1 or CBP and co-repressors like SMRT. <ref name="Zoete">PMID:17317294</ref>Co-activators like CBP contain a conserved LXXLL motif where X is any amino acid, and use this to bind a hydrophobic pocket on the receptor surface formed by the stabilized AF-2 helix H12.<ref name="Gampe">PMID:10882139</ref> In the case of the PPARγ/rosiglitazone/SRC-1 complex, the LXXLL motif helix of SRC-1 forms <scene name='Peroxisome_Proliferator-Activated_Receptors/Src_binding/1'>hydrophobic interactions with Leu468 and Leu318 of the LBD and hydrogen bonds between Glu471 and Lys301 and the co-activator backbone.</scene> These charged residues are conserved across PPAR isotypes and form the “charge clamp,” an essential component for co-activator stabilization in the PPAR LBD.<ref>PMID:11698662</ref> | ||
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===DNA Binding Domain Structure=== | ===DNA Binding Domain Structure=== | ||
[[Image:Rosiglitazone.png| | [[Image:Rosiglitazone.png|250px|left| Human PPARγ agonist, Rosiglitazone ([[Avandia]])]] | ||
PPARs also contain a DNA binding domain (DBD) The <scene name='Peroxisome_Proliferator-Activated_Receptors/Zinc_fingers/1'>DBD consists of two zinc fingers</scene> ([[3dzy]]), one on PPAR and one on RXR, that bind PPREs of PPAR-responsive genes. The consensus sequence of PPREs is AGGTCA and has been found in a number of PPAR inducible genes like acyl-CoA oxidase and adipocyte fatty acid-binding protein.<ref>PMID:9383428</ref> Chandre et al. have demonstrated that the DNA PPRE allosterically contributes to its own binding via a <scene name='Peroxisome_Proliferator-Activated_Receptors/Dbd_hbonds/1'>head-to-tail interaction between the PPAR DBD and RXR DBD</scene> using residues Gln206 and Arg209 on RXRα and Asn160 on PPARγ.<ref>PMID:19043829</ref> | PPARs also contain a DNA binding domain (DBD) The <scene name='Peroxisome_Proliferator-Activated_Receptors/Zinc_fingers/1'>DBD consists of two zinc fingers</scene> ([[3dzy]]), one on PPAR and one on RXR, that bind PPREs of PPAR-responsive genes. The consensus sequence of PPREs is AGGTCA and has been found in a number of PPAR inducible genes like acyl-CoA oxidase and adipocyte fatty acid-binding protein.<ref>PMID:9383428</ref> Chandre et al. have demonstrated that the DNA PPRE allosterically contributes to its own binding via a <scene name='Peroxisome_Proliferator-Activated_Receptors/Dbd_hbonds/1'>head-to-tail interaction between the PPAR DBD and RXR DBD</scene> using residues Gln206 and Arg209 on RXRα and Asn160 on PPARγ.<ref>PMID:19043829</ref> | ||
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