Hertz Rachel, Kalderon Bella, Byk Tamara, Berman Ina, Za'tara Ghadeer, Mayer Raphael, Bar-Tana Jacob
Department of Human Nutrition and Metabolism, Hebrew University Medical School, Ein-Kerem, P. O. Box 12272, Jerusalem 91120, Israel.
J Biol Chem. 2005 Jul 1;280(26):24451-61. doi: 10.1074/jbc.M500732200. Epub 2005 May 3.
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.
肝细胞核因子-4α（HNF-4α）的活性受天然和外源性脂肪酸及脂肪酰辅酶A配体的调节，调节方式取决于它们的链长、不饱和度和取代基。本文报道HNF-4α的酰基辅酶A结合位点由E-F结构域组成，可结合长链脂肪酰辅酶A，但不结合相应的游离酸，并催化结合的脂肪酰辅酶A水解。先前在HNF-4α E结构域的X射线结构中报道的游离酸口袋可捕获脂肪酸，但排除脂肪酰辅酶A。酰基辅酶A结合位点和游离酸结合位点是不同的，且不一致。HNF-4α硫酯酶的游离脂肪酸产物可能与捕获在HNF-4α脂肪酸口袋中的游离酸进行交换。HNF-4α的高亲和力、不可水解的脂肪酰辅酶A配体可抑制其硫酯酶活性，从而消除酰基辅酶A结合位点和游离脂肪酸结合位点之间的相互作用。因此，HNF-4α的转录活性受其两种相互关联的酰基配体以及由硫酯酶活性串联相间的两个结合位点控制。HNF-4α的酰基辅酶A/游离酸和受体/酶双重性扩展了核受体的范式。
