Thioesterase activity and acyl-CoA/fatty acid cross-talk of hepatocyte nuclear factor-4{alpha}.
Hepatocyte nuclear factor-4alpha (HNF-4alpha) activity is modulated by natural and xenobiotic fatty acid and fatty acyl-CoA ligands as a function of their chain length, unsaturation, and substitutions. The acyl-CoA site of HNF-4alpha is reported here to consist of the E-F domain, to bind long-chain acyl-CoAs but not the respective free acids, and to catalyze the hydrolysis of bound fatty acyl-CoAs. The free acid pocket, previously reported in the x-ray structure of HNF-4alpha E-domain, entraps fatty acids but excludes acyl-CoAs. The acyl-CoA and free acid sites are distinctive and noncongruent. Free fatty acid products of HNF-4alpha thioesterase may exchange with free acids entrapped in the fatty acid pocket of HNF-4alpha. Cross-talk between the acyl-CoA and free fatty acid binding sites is abrogated by high affinity, nonhydrolyzable acyl-CoA ligands of HNF-4alpha that inhibit its thioesterase activity. Hence, HNF-4alpha transcriptional activity is controlled by its two interrelated acyl ligands and two binding sites interphased in tandem by the thioesterase activity. The acyl-CoA/free-acid and receptor/enzyme duality of HNF-4alpha extends the paradigm of nuclear receptors.
Hertz
Rachel
R
Department of Human Nutrition and Metabolism, Hebrew University Medical School, Ein-Kerem, P. O. Box 12272, Jerusalem 91120, Israel.
Kalderon
Bella
B
Byk
Tamara
T
Berman
Ina
I
Za'tara
Ghadeer
G
Mayer
Raphael
R
Bar-Tana
Jacob
J
D000214:Acyl Coenzyme A / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D001896:Boron Compounds / Q000494:pharmacology; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D018360:Crystallography, X-Ray; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000494:pharmacology; D051557:Hepatocyte Nuclear Factor 4; D007700:Kinetics; D008024:Ligands; D008954:Models, Biological; D010750:Phosphoproteins / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry; D013379:Substrate Specificity; D013869:Thiolester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014226:Triazenes / Q000494:pharmacology
C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D000214:Acyl Coenzyme A; D001896:Boron Compounds; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D005456:Fluorescent Dyes; D051557:Hepatocyte Nuclear Factor 4; D008024:Ligands; D010750:Phosphoproteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D014226:Triazenes; C034613:triacsin C; D013869:Thiolester Hydrolases