Peroxisome Proliferator-Activated Receptors: Difference between revisions
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The [[Peroxisome Proliferator-Activated Receptors]] (PPAR) α, δ, and γ are members of the nuclear receptor family. Since their discovery in the early 90s, it has become clear that the PPARs are essential modulators of external stimuli, acting as transcription factors to regulate mammalian metabolism, cellular differentiation, and tumorigenesis. The PPARs are the targets of numerous pharmaceutical drugs aimed at treating hypolipidemia and [[diabetes]] among other diseases.<ref name="Berger"/> | The [[Peroxisome Proliferator-Activated Receptors]] (PPAR) α, δ, and γ are members of the nuclear receptor family. Since their discovery in the early 90s, it has become clear that the PPARs are essential modulators of external stimuli, acting as transcription factors to regulate mammalian metabolism, cellular differentiation, and tumorigenesis. The PPARs are the targets of numerous pharmaceutical drugs aimed at treating hypolipidemia and [[diabetes]] among other diseases.<ref name="Berger"/> | ||
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==Biological Role== | ==Biological Role== | ||
[[Image: PPAR_Mechanism.png|400px|left|thumb| PPAR Mechanism of Action in the Human Body]] | [[Image: PPAR_Mechanism.png|400px|left|thumb| PPAR Mechanism of Action in the Human Body]] | ||
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===Co-Activator & Co-Repressor Binding=== | ===Co-Activator & Co-Repressor Binding=== | ||
[[Image: SRC_binding.png|350px|left | [[Image: SRC_binding.png|350px|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|300px|left | [[Image:Rosiglitazone.png|300px|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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