Bach1, a heme‐dependent transcription factor, reveals presence of multiple heme binding sites with distinct coordination structure

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Abstract
The mammalian transcription factor Bach1 functions as a repressor of the enhancers of heme oxygenase‐1 (HO‐1) gene (Hmox‐1) by forming heterodimers with the small Maf proteins such as MafK. The transcription of Hmox‐1 is regulated by the substrate of HO‐1, heme. Heme induces expression of Hmox‐1 in part by inhibiting the binding of Bach1 to the enhancers and inducing the nuclear export of Bach1. A dipeptide motif of cysteine and proline (CP motif) in Bach1 is essential for the heme‐mediated regulation. In this study, we show that five molecules of heme bind to Bach1 by the heme‐titration assay. The Bach1‐heme complex exhibits an absorption spectrum with a major Soret peak at 371 nm and Raman band at 343 cm‐1 in high amounts of heme and a spectrum containing the major Soret peak at 423 nm at low heme concentrations. The spectroscopic characterization indicates that Bach1 has two kinds of heme‐binding sites with different coordination structures. Mutagenesis studies have established that four molecules of heme bind to the cysteine residues of four CP motifs in the C terminus of Bach1. These results raise the possibility that two separated activities of Bach1, DNA‐binding and nuclear export, are regulated by heme binding at the different CP motifs of Bach1 respectively, but not by cooperative heme‐binding.

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