TY - JOUR
T1 - Thioesterase activity and acyl-CoA/fatty acid cross-talk of hepatocyte nuclear factor-4α
AU - Hertz, Rachel
AU - Kalderon, Bella
AU - Byk, Tamara
AU - Berman, Ina
AU - Za'Tara, Ghadeer
AU - Mayer, Raphael
AU - Bar-Tana, Jacob
PY - 2005/7/1
Y1 - 2005/7/1
N2 - Hepatocyte nuclear factor-4α (HNF-4α) 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-4α 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-4α 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 NHF-4α thioesterase may exchange with free acids entrapped in the fatty acid pocket of HNF-4α. Cross-talk between the acyl-CoA and free fatty acid binding sites is abrogated by high affinity, nonhydrolyzable acyl-CoA ligands of HNF-4α that inhibit its thioesterase activity. Hence, HNF-4α 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-4α extends the paradigm of nuclear receptors.
AB - Hepatocyte nuclear factor-4α (HNF-4α) 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-4α 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-4α 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 NHF-4α thioesterase may exchange with free acids entrapped in the fatty acid pocket of HNF-4α. Cross-talk between the acyl-CoA and free fatty acid binding sites is abrogated by high affinity, nonhydrolyzable acyl-CoA ligands of HNF-4α that inhibit its thioesterase activity. Hence, HNF-4α 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-4α extends the paradigm of nuclear receptors.
UR - http://www.scopus.com/inward/record.url?scp=21644454402&partnerID=8YFLogxK
U2 - 10.1074/jbc.M500732200
DO - 10.1074/jbc.M500732200
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C2 - 15870076
AN - SCOPUS:21644454402
SN - 0021-9258
VL - 280
SP - 24451
EP - 24461
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 26
ER -