ROLE OF HEME-BINDING PROTEINS IN HEPATIC HEME TRANSPORT

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The transport of heme to the liver by hemopexin has important consequences for the hepatocyte. Not only is biologically available iron conserved and toxic effects of peripheral heme prevented but also the transported heme regulates the expression of proteins involved in heme, heme-protein and iron metabolism. The ultimate goal of this research project is to elucidate the role and mechanism of action of the multimeric, membrane heme-binding protein (MHBP) of the hemopexin system in hepatic heme uptake, intracellular heme transport and gene regulation by heme. To achieve the goals of this research program, a basic approach is being taken in which the subunits of MHBP are being isolated and characterized, and their function in intracellular heme transport and regulation of protein expression delineated. The specific aims for the 5 years of requested support are: 1. To continue to characterize biochemically important molecular properties of MHBP and its subunits, p17.5 (which bind heme) and p47; 2. To continue to delineate the role and mechanism of action of MHBP in intracellular heme transport by liver cells employing biochemical and morphological approaches; 3. To continue to define the regulation of hepatic proteins by receptor-mediated transport of heme and heme analogs; 4. To clone and sequence the cDNA for p17.5, the heme-binding subunit of MHBP, from liver cDNA libraries in hand, using available antibodies or oligonucleotide probes; and 5. To use the cloned cDNA to p17.5 of MHBP to investigate its expression. Several proteins have evolved to bind heme in order to direct the chemistry of the highly-reactive iron of this poorly water-soluble molecule. The basic information to be obtained from the research proposed here on MHBP will provide answers to fundamental questions concerning the homeostasis of hepatic heme and iron metabolism in health and disease.