Function and High-Resolution of an APC superfamily amino acid transporter
APC 超家族氨基酸转运蛋白的功能和高分辨率
基本信息
- 批准号:7450594
- 负责人:
- 金额:$ 20.67万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-04-01 至 2010-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAmino Acid TransporterAmino AcidsBacteriaBasic Amino Acid Transport SystemsBumetanideCarrier ProteinsCationsCell membraneCellsCerebral EdemaChloride IonChloridesCollaborationsConditionCrystal FormationCrystallizationCystic FibrosisDefectDetergentsDiagnosticDiarrheaDiseaseDiureticsDrug InteractionsDrug RegulationsEpitheliumFamilyFamily memberFurosemideGoalsHomeostasisHumanHypertensionInvestigationIon CotransportKidneyLaboratoriesMechanicsMediatingMembrane Transport ProteinsMolecularMolecular ConformationMolecular StructureMovementNeuronsNumbersPharmaceutical PreparationsPlayPolyaminesPolycystic Kidney DiseasesPotassium ChannelPotassium ChlorideProtein IsoformsProteinsPumpRangeRateRegulationResearchResolutionRoleSiteSodiumSodium ChlorideStructureSubstrate SpecificityTechniquesTherapeutic AgentsWorkabsorptionbasechloride-cotransporter potassiumdesignintestinal epitheliummembernervous system disorderresearch studystoichiometry
项目摘要
DESCRIPTION (provided by applicant): The aminoacid/ polyamine/organocation (APC) superfamily of transporters includes human LAT and CAT amino acid transporters as well the Na-K-Cl, Na-Cl and K-Cl cation-chloride cotransporters (CCCs). The CAT and LAT amino acid transporters mediate a major fraction of amino acid movement across cell membranes and across renal and intestinal epithelia. The Na-K-Cl cotransporter, Na-Cl, and K-Cl cotransporters play a central role in cellular volume and chloride homeostasis, and in neuronal cells are responsible for regulation of excitability through changes in intracellular chloride. In secretory epithelia, NKCC1 functions together with Cl channels, the Na pump, and K channels to bring about the major fraction of regulated salt secretion movement, while in the mammalian kidney another isoform, NKCC2, mediates salt absorption and is the site of action of the loop diuretic drugs furosemide and bumetanide. None of these transport proteins is understood at the molecular level because we do not know the structure of any of the APC family members. The goal of this project is to obtain the first high-resolution crystal structure of a prokaryotic APC superfamily member, and to understand the function of the transporter in the context of the structure. We have chosen prokaryotic APCs because we can select among a large number of potential candidates, and because we can express these proteins at high levels in bacteria. Strong alignment assures that we will be able to apply the structural information to high-resolution predictions for the structure of the eukaryotic transporters. This high-payoff project is paradigm-shifting in that it will open the door to a broad field of investigation in amino acid transporters and cation-chloride cotransporters in work in which structural information is used to inform mechanistic studies, including studies of regulation and drug interactions. The specific aims are 1) to clone a diverse set of prokaryotic cationic amino acid transporters and examine their ability to be produced in high yield and with high stability, 2) to obtain the high resolution crystal structure of an APC transporter, and 3) to determine the function of selected prokaryotic transporters, relating the function to the emerging structure. Diseases and disease conditions including hypertension, cerebral edema, polycystic kidney disease, secretory diarrhea, cystic fibrosis, and some diseases of the nervous system involve defects or over activity of the cellular machinery that is responsible for salt and amino acid movements across cell membranes. This research is directed to understanding one part of that cellular machinery, a set of related proteins called cation- chloride cotransporters and amino acid transporters that are responsible for directly handling coordinated sodium, potassium and chloride movements, or amino acid movements. By understanding the molecular structure of these proteins, we will be able to understand the mechanics of their action, and the mechanism of their regulation, thus being better able to design diagnostic and therapeutic agents and treat the disease states.
描述(由申请人提供):转运蛋白的氨基酸/多胺/有机体(APC)超家族包括人LAT和CAT氨基酸转运蛋白以及Na-K-Cl、Na-Cl和K-Cl阳离子-氯化物共转运蛋白(CCC)。CAT和LAT氨基酸转运蛋白介导氨基酸跨细胞膜和跨肾和肠上皮的运动的主要部分。Na-K-Cl协同转运蛋白、Na-Cl和K-Cl协同转运蛋白在细胞体积和氯稳态中起核心作用,并且在神经元细胞中负责通过细胞内氯的变化来调节兴奋性。在分泌性上皮中,NKCC 1与Cl通道、Na泵和K通道一起发挥作用,产生调节盐分泌运动的主要部分,而在哺乳动物肾脏中,另一种亚型NKCC 2介导盐吸收,并且是袢利尿药物呋塞米和布美他尼的作用部位。这些转运蛋白都没有在分子水平上被理解,因为我们不知道APC家族成员的结构。该项目的目标是获得原核APC超家族成员的第一个高分辨率晶体结构,并了解转运蛋白在结构背景下的功能。我们选择原核APC是因为我们可以在大量潜在的候选者中进行选择,并且因为我们可以在细菌中高水平表达这些蛋白质。强比对保证了我们将能够将结构信息应用于真核转运蛋白结构的高分辨率预测。这个高回报的项目是范式转变,因为它将打开大门,在氨基酸转运蛋白和阳离子氯协同转运蛋白的工作中,结构信息被用来通知机制研究,包括研究的监管和药物相互作用的广泛领域的调查。具体目的是1)克隆一组不同的原核阳离子氨基酸转运蛋白,并检查它们以高产率和高稳定性生产的能力,2)获得APC转运蛋白的高分辨率晶体结构,和3)确定所选原核转运蛋白的功能,将功能与出现的结构相关联。包括高血压、脑水肿、多囊肾病、分泌性腹泻、囊性纤维化和一些神经系统疾病的疾病和疾病状况涉及负责盐和氨基酸跨细胞膜运动的细胞机制的缺陷或过度活性。这项研究的目的是了解细胞机制的一部分,一组相关的蛋白质称为阳离子氯协同转运蛋白和氨基酸转运蛋白,负责直接处理协调的钠,钾和氯的运动,或氨基酸运动。通过了解这些蛋白质的分子结构,我们将能够了解它们的作用机制及其调节机制,从而能够更好地设计诊断和治疗药物并治疗疾病状态。
项目成果
期刊论文数量(0)
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{{ truncateString('BLISS FORBUSH', 18)}}的其他基金
Molecular Physiology of the Na-K-Cl Cotransporter
Na-K-Cl 协同转运蛋白的分子生理学
- 批准号:
7901772 - 财政年份:2009
- 资助金额:
$ 20.67万 - 项目类别:
Function and High-Resolution of an APC superfamily amino acid transporter
APC 超家族氨基酸转运蛋白的功能和高分辨率
- 批准号:
7571708 - 财政年份:2008
- 资助金额:
$ 20.67万 - 项目类别:
Function and Regulation of NKCC2 in the Mammalian Kidney
NKCC2 在哺乳动物肾脏中的功能和调节
- 批准号:
7499847 - 财政年份:2007
- 资助金额:
$ 20.67万 - 项目类别:
Mechanisms of Membrane Transport Gordon Conference 2003
膜传输机制戈登会议 2003
- 批准号:
6677730 - 财政年份:2003
- 资助金额:
$ 20.67万 - 项目类别:
FUNCTION AND REGULATION OF NKCC2 IN THE MAMMALIAN KIDNEY
NKCC2 在哺乳动物肾脏中的功能和调节
- 批准号:
6725895 - 财政年份:2003
- 资助金额:
$ 20.67万 - 项目类别:
NA+/K+/CL- AND K+/CL- COTRANSPORTERS IN MAMMALIAN KIDNEY
哺乳动物肾脏中的 NA /K /CL- 和 K /CL- 协同转运蛋白
- 批准号:
6574316 - 财政年份:2001
- 资助金额:
$ 20.67万 - 项目类别:
NA+/K+/CL- AND K+/CL- COTRANSPORTERS IN MAMMALIAN KIDNEY
哺乳动物肾脏中的 NA /K /CL- 和 K /CL- 协同转运蛋白
- 批准号:
6354687 - 财政年份:2000
- 资助金额:
$ 20.67万 - 项目类别:
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