ROLE OF HEME-BINDING PROTEINS IN HEPATIC HEME TRANSPORT

血红素结合素将血红素转运到肝脏具有重要的作用。 肝细胞的后果。 不仅是生物学上的 铁的保存和外周血红素的毒性作用得到防止， 转运的血红素调节蛋白质的表达， 血红素、血红素蛋白和铁代谢。 这个项目的最终目标 研究项目是阐明的作用和机制的行动， 血红素结合蛋白系统的多聚体膜血红素结合蛋白 在肝血红素摄取、细胞内血红素转运和基因调控中 通过血红素。 为了实现这项研究计划的目标，一个基本的 正在采取分离MHBP亚单位的方法 和表征，以及它们在细胞内血红素转运中的功能 和蛋白质表达的调控。 所要求的5年支助的具体目标是： 1. 为了继续表征生物化学上重要的分子 MHBP及其亚基p17.5（结合血红素）和p47的性质; 2. 继续阐明MHBP在以下方面的作用和作用机制： 肝细胞利用生物化学和 形态学方法; 3. 继续定义肝蛋白的调节， 受体介导的血红素和血红素类似物的转运; 4. 克隆血红素结合亚基p17.5的cDNA并测序， 的MHBP，从肝cDNA文库在手，使用可用的抗体， 或寡核苷酸探针;和 5. 利用克隆的MHBP p17.5的cDNA，研究其在MHBP中的作用。 表情 几种蛋白质已经进化到结合血红素，以指导 这种水溶性差的高活性铁的化学性质 分子。 从研究中获得的基本信息 这里提出的关于MHBP的建议将为基本问题提供答案 关于健康人肝血红素和铁代谢的动态平衡 和疾病

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.