The Ligand Is a Gas

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Science  19 Aug 2005:
Vol. 309, Issue 5738, pp. 1157
DOI: 10.1126/science.309.5738.1157c

Nuclear receptors function as ligand-regulated transcription factors, but for many members of this family, the ligands are not known. In fact, before the fine piece of detective work described by Reinking et al., only 1 of the 18 nuclear receptor proteins in Drosophila had an identified ligand. The clue that led to the unexpected partner for the receptor known as E75 was the blood-red color of the purified protein. Electron absorption and mass spectrometry analysis revealed that the receptor has a tightly associated heme group. Further analysis led the authors to propose three possible functions of the receptor complex. First, heme was required for stability of the E75 protein, and thus E75 could serve as a sensor of cellular heme concentration. Second, heme-containing proteins are known to bind diatomic gases, and E75 is no exception. Binding of CO and NO to E75 was detected spectrophotometrically. E75 interacts with another nuclear receptor, HR3, and inhibits activation of target genes by HR3. CO binding inhibited interaction of a peptide from HR3 with E75. Treatment of cells with NO donors relieved the inhibitory effects of E75 on HR3-induced transcription. Thus, E75 may sense CO and NO as intracellular signaling molecules. Finally, E75 might function as a redox sensor because only the reduced form of E75 was stabilized by interaction with the HR3 peptide. — LBR

Cell 122, 195 (2005).

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