Peroxisome Proliferator-Activated Receptors: Difference between revisions
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The transcriptional activity of PPAR is regulated by its interaction with co-activators like SRC-1 or CBP and co-repressors like SMRT. <ref> 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 >PMID:10882139</ref> In the case of the PPARγ/rosiglitazone/SRC-1 complex, the hydrophobic face of the LXXLL motif helix of SRC-1 forms <scene name='Peroxisome_Proliferator-Activated_Receptors/Src_binding/1'>hydrophobic interactions with Leu468 and L318 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:15276186</ref> | The transcriptional activity of PPAR is regulated by its interaction with co-activators like SRC-1 or CBP and co-repressors like SMRT. <ref> 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 >PMID:10882139</ref> In the case of the PPARγ/rosiglitazone/SRC-1 complex, the hydrophobic face of the LXXLL motif helix of SRC-1 forms <scene name='Peroxisome_Proliferator-Activated_Receptors/Src_binding/1'>hydrophobic interactions with Leu468 and L318 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:15276186</ref> | ||
When PPAR is bound to a co-repressor, the <scene name='Peroxisome_Proliferator-Activated_Receptors/H12_in_alpha/ | When PPAR is bound to a co-repressor, the <scene name='Peroxisome_Proliferator-Activated_Receptors/H12_in_alpha/4'>hydrogen bond between Tyr 464 (in PPARα) in AF-2 and other AF-2 stabilizing helices is destroyed</scene>, preventing the AF-2 H12 helix from occupying its active state. This in turn eliminates the charge clamp between PPAR and a prospective co-activator.<ref>PMID:11698662</ref> Notice the <scene name='Peroxisome_Proliferator-Activated_Receptors/H12_in_alpha_active/2'>position of H12 when bound to a co-activator.</scene> | ||
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