Functions of the Human OST-alpha and OST-beta Proteins

人类 OST-α 和 OST-β 蛋白的功能

• 批准号: 7386591
• 负责人: NAZZARENO BALLATORI
• 金额: $ 28.2万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7386591
• 关键词: Amino Acid Sequence; Apical; Bile Acids; Cell membrane; Cell physiology; Chemicals; Complement; Complementary DNA; Complex; Digoxin; Dinoprostone; Eicosanoids; Epithelial; Estrone-Sulfate; Evolution; G-Protein-Coupled Receptors; Gene Family; Genes; Homeostasis; Homologous Gene; Human; Human Genome; Inorganic Sulfates; Intestines; Kidney; Knockout Mice; Ligands; Liver; Localized; MDCK cell; Mammals; Mediating; Membrane; Membrane Transport Proteins; Mouse Protein; Movement; Mus; Oocytes; Organic Anion Transporters; Physiological; Play; Prostaglandins; Proteins; Raja; Ramp; Rhodopsin; Role; Sensory Rhodopsins; Signaling Molecule; Skates; Skating; Small Intestines; Steroids; Taurine Cholate; Testing; Tissues; Transmembrane Domain; Transport Process; Unspecified or Sulfate Ion Sulfates; Xenopus laevis; basolateral membrane; comparative; dehydroepiandrosterone; intracellular protein transport; member; novel; protein localization location; receptor; solute; uptake

DESCRIPTION (provided by applicant): All cell functions ultimately depend on the regulated movement of chemicals across the plasma membrane. Although recent studies have described some of the genes involved in these transport processes, it is clear that many other essential gene products remain to be identified and characterized. Using a comparative approach, we recently cloned and functionally characterized a new type of organic solute and steroid transporter (OST) from skate, mouse, and human genomes. This transporter is generated by co-expression of two unique gene products, organic solute transporter-alpha and -beta (OSTalpha, OSTbeta). In contrast with most other transporters that are members of gene families, OSTalpha and OSTbeta do not have homologues in the mouse or human genomes. Moreover, these genes are evolutionary conserved and are able to functionally complement each other across species. Preliminary characterization of the transport function and cellular localization of the proteins suggests that OSTalpha-OSTbeta is a critical regulator of the reabsorption of bile acids and other steroids in the intestine, kidney, and other epithelial tissues. Transported substrates include estrone 3-sulfate, dehydroepiandrosterone 3-sulfate, taurocholate, digoxin, and prostaglandin E2, indicating a role in the disposition of key cellular metabolites or signaling molecules. These preliminary studies are consistent with the hypothesis that OSTalpha-OSTbetaa is a heteromeric transporter that is localized to the basolateral membrane of key epithelial tissues, and serves to regulate the disposition of steroid-derived molecules. To test this hypothesis the proposed studies aim to: (1) Define the tissue expression, and cellular and sub-cellular distribution of OSTalpha and OSTbeta, (2) Generate and functionally characterize Osta knockout mice, (3) Examine whether OSTalpha and OSTbeta are forming heterodimers or heteromultimers, and (4) Identify the regions of the OSTalpha and OSTbeta proteins that are critical for plasma membrane delivery and/or functional expression of transport activity. Overall, these studies should provide fundamental information on the mechanisms by which this novel transporter regulates bile acid and steroid homeostasis in mammals.

描述（由申请人提供）：所有细胞功能最终都取决于化学物质穿过质膜的调节运动。尽管最近的研究描述了参与这些运输过程的一些基因，但显然许多其他重要的基因产物仍有待鉴定和表征。我们最近采用比较方法，从鳐鱼、小鼠和人类基因组中克隆了一种新型有机溶质和类固醇转运蛋白（OST），并对其进行了功能表征。该转运蛋白是由两种独特的基因产物——有机溶质转运蛋白-α和-β（OSTα、OSTβ）的共表达产生的。与大多数其他属于基因家族成员的转运蛋白相比，OSTalpha 和 OSTbeta 在小鼠或人类基因组中没有同源物。此外，这些基因在进化上是保守的，并且能够在不同物种之间功能互补。蛋白质转运功能和细胞定位的初步表征表明，OSTα-OSTβ 是肠、肾和其他上皮组织中胆汁酸和其他类固醇重吸收的关键调节因子。转运底物包括雌酮 3-硫酸盐、脱氢表雄酮 3-硫酸盐、牛磺胆酸盐、地高辛和前列腺素 E2，表明在关键细胞代谢物或信号分子的处置中发挥作用。这些初步研究与 OSTalpha-OSTbetaa 是一种异聚转运蛋白的假设一致，该转运蛋白位于关键上皮组织的基底外侧膜，并用于调节类固醇衍生分子的处置。为了检验这一假设，拟议的研究旨在：（1）定义 OSTalpha 和 OSTbeta 的组织表达以及细胞和亚细胞分布，（2）生成 Osta 敲除小鼠并进行功能表征，（3）检查 OSTalpha 和 OSTbeta 是否是形成异二聚体或异多聚体，以及(4)鉴定对于质膜递送和/或转运活性的功能表达至关重要的OSTα和OSTβ蛋白区域。总的来说，这些研究应该提供有关这种新型转运蛋白调节哺乳动物胆汁酸和类固醇稳态的机制的基本信息。