Analysis of the Yeast MRP Subfamily of ABC Transporters

描述（由申请人提供）：atp结合盒（ABC）转运体的多药耐药相关蛋白（MRP）亚家族在保护细胞免受药物和环境毒素(如重金属（汞、砷、铅和镉）的侵害方面起着关键作用。mrp（也称为abcc）与其他ABC转运蛋白有两个显著的区别：1)它们含有一个额外的“n端延伸”，带有一个称为L0的保守区域，2)它们以谷胱甘肽（GSH）缀合物或复合物的形式运输底物。在这里，我们将利用酿酒酵母中强大的遗传、分子和细胞工具来解决MRPs的几个关键问题。我们的具体目标是：1)确定MRPs L0内的保守残基是否对GSH结合具有特异性；2)评估最近发现的酵母MRP Ycflp的新相互作用是否在MRP运输的一般机制中发挥了不可或缺的作用；3)通过基因和化学筛选，测试MRP的主要作用是处理潜在有害的“代谢碎屑”的可能性。总的来说，我们的分析可能为MRP为基础的疾病（如DJS、PXE、囊性纤维化）提供更有效的治疗方法和/或有助于减少环境毒素的损害。

DESCRIPTION (provided by applicant): The multidrug resistance-associated protein (MRP) subfamily of the ATP-binding cassette (ABC) transporters plays a key role in protecting cells from drugs and environmental toxins such as heavy metals (mercury, arsenic, lead, and cadmium). The MRPs (also called ABCCs) are distinguished from other ABC transporters by two striking hallmarks: 1) they contain an additional "N-terminal extension" with a conserved region called L0, and 2) they transport substrates in the form of glutathione (GSH)-conjugates or complexes. Here, we will use the powerful genetic, molecular, and cellular tools available in Saccharomyces cerevisiae to address several key issues of the MRPs. Our specific aims are to: 1) determine whether conserved residues within the L0 of MRPs are specific for GSH binding; 2) assess whether novel interactors, recently identified for the yeast MRP Ycflp, play an integral role in the general mechanism of MRP transport; and 3) test the possibility that a major role of the MRP's is to dispose of potentially harmful "metabolic detritus", using genetic and chemical screens. Overall, our analysis may suggest more effective therapies for MRP- based diseases (e.g. DJS, PXE, cystic fibrosis) and/or aid in reducing damage from environmental toxins.