A structural basis for the activation of peroxisome proliferator-activated receptor gamma (PPARγ) by perfluorooctanoic acid (PFOA)
These videos have been matched automatically. Contact us if they are not relevant.
These videos have been matched automatically. Contact us if they are not relevant.
View abstract on PubMed
Summary
This summary is machine-generated.Perfluorooctanoic acid (PFOA) partially activates the PPARγ receptor by binding to its ligand-binding domain, revealing molecular mechanisms for PFOA
Area Of Science
- Environmental Science
- Molecular Biology
- Biochemistry
Background
- Perfluorooctanoic acid (PFOA) is a persistent environmental pollutant linked to adverse health effects.
- PFOA's impact on metabolic homeostasis is partly mediated by the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ).
- The precise molecular mechanism of PFOA-induced PPARγ activation remained unclear.
Purpose Of The Study
- To elucidate the structural basis of PFOA-mediated PPARγ activation.
- To understand how PFOA interacts with the PPARγ ligand-binding domain (LBD).
- To characterize the functional consequences of PFOA binding to PPARγ.
Main Methods
- X-ray crystallography was used to determine the co-crystal structure of the PPARγ LBD complexed with PFOA.
- Fluorescence polarization assays were employed to assess PFOA's interaction with PPARγ and coactivator recruitment.
- Structural comparisons were made with known PPARγ:ligand complexes.
Main Results
- PFOA binds to the PPARγ LBD in three distinct sites, including the activation function 2 (AF2) region.
- Structural data suggests PFOA acts as a partial agonist for PPARγ at micromolar concentrations.
- In vitro assays confirmed PFOA's partial agonism and weak coactivator recruitment.
Conclusions
- This study provides the first structural insights into PFOA-mediated PPARγ activation.
- The findings clarify the partial agonist mechanism of PFOA on PPARγ.
- This knowledge can inform the design of safer perfluoroalkyl substance (PFAS) alternatives.
These videos have been matched automatically. Contact us if they are not relevant.
These videos have been matched automatically. Contact us if they are not relevant.
Related Concept Videos
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
...
Peroxisomes are specialized organelles present in fungi, plant, and animal cells. It can vary in number, size, morphology, and activity depending on the type of tissue and the nutritional state of the cell. For example, cells with active lipid metabolism, such as adipocytes, neurons, and hepatocytes, have more peroxisomes than other cells in the body. Besides their primary role in breaking down complex organic molecules, peroxisomes can also synthesize specific macromolecules and participate in...
Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and...
Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
Cells contain membrane-bound organelles called peroxisomes that oxidize organic molecules by transferring hydrogen atoms to oxygen, producing hydrogen peroxide. Peroxisomes enzymatically convert the released hydrogen peroxide into water and oxygen.
Peroxisomal Protein Import:
Peroxisomes lack the genetic machinery required to code for their own proteins. Hence, most peroxisomal membrane, lumenal and transmembrane proteins are synthesized in the cytoplasm or ER and transported to the peroxisome...