Structure and Mechanism of a Virtual Proton Pump

虚拟质子泵的结构和机制

• 批准号: 7995238
• 负责人: Christopher Miller
• 金额: $ 31.28万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7995238
• 关键词: Acids; Adenomatous Polyposis Coli Protein; Agmatine; Amino Acids; Arginine; Artificial Membranes; Bacteria; Binding Sites; Biological; Cations; Cell membrane; Cell physiology; Cells; Complex; Coupled; Crystallography; Cytoplasm; DNA Sequence Rearrangement; Decarboxylation; Enterobacteriaceae; Environment; Escherichia coli; Essential Amino Acids; Eukaryota; Exposure to; Family; Free Energy; Gastric Acid; Gastric Juice; Genes; Goals; Health; Heart; Human; Location; Malignant Neoplasms; Membrane; Membrane Proteins; Membrane Transport Proteins; Molecular; Molecular Conformation; Molecular Genetics; Monoclonal Antibodies; Movement; Mutation; Nature; Nutrient; Organism; Pathology; Physiological; Physiology; Polyamines; Positioning Attribute; Process; Protein Biochemistry; Protein Family; Proteins; Proton Pump; Protons; Resistance; Resolution; Stomach; Structure; Substrate Specificity; System; Testing; Variant; Work; cancer cell; design; improved; member; overexpression; protein structure; public health relevance; reconstitution; response; virtual

DESCRIPTION (provided by applicant): The aim of this proposal is to determine the structure of AdiC, a member of a widespread and little-understood class of membrane transport proteins - the APC superfamily. APC proteins, nearly ubiquitous in the biological world, are used to move amino acids, polyamines, and a variey of organic cations across cell membranes for a multitude of physiological purposes. Although this is a huge molecular superfamily, no high-resolution structures are known for any APC proteins, and our understanding of their fundamental mechanisms of substrate transport is currently shallow. The bacterial APC protein AdiC, which moves arginine into many enteric bacteria, is a key player in the "extreme acid resistance" response that these organisms use to survive exposure to the acid environment of the stomach. This particular APC protein may be overexpressed, purified, functionally reconstituted in artificial membranes, and, most importantly, crystallized. The project aims to determine the structure of AdiC by x-ray crystallography, and to use this structural information to understand how this protein specifically recognizes its organocationic substrates and how it moves threse across the biological membrane. PUBLIC HEALTH RELEVANCE: This project is relevant to human health in two ways. First, by providing fundamental information on the edge of discovery about the molecular workings of a new class of membrane protein, it will illuminate the ways that cells nourish themselves with essential amino acid nutrients. Second, this particular protein family is intimately involved not only in essential human physiologies in health, but also in devastating pathologies, in particular a variety of cancers that require APC transporters to supply amino acids to fast-growing, malignant cells.

描述（由申请人提供）：本提案的目的是确定 AdiC 的结构，AdiC 是一类广泛传播且鲜为人知的膜转运蛋白 - APC 超家族的成员。 APC 蛋白在生物世界中几乎无处不在，可用于跨细胞膜移动氨基酸、多胺和各种有机阳离子，以达到多种生理目的。尽管这是一个巨大的分子超家族，但任何 APC 蛋白都没有高分辨率的结构，而且我们目前对其底物运输的基本机制的了解还很浅薄。细菌 APC 蛋白 AdiC 将精氨酸转移到许多肠道细菌中，它是这些微生物用来在胃酸性环境中生存的“极端耐酸性”反应的关键因素。这种特殊的 APC 蛋白可以过表达、纯化、在人工膜中进行功能重建，最重要的是结晶。该项目旨在通过 X 射线晶体学确定 AdiC 的结构，并利用该结构信息来了解该蛋白质如何特异性识别其有机阳离子底物以及如何将其移动穿过生物膜。 公共卫生相关性：该项目在两个方面与人类健康相关。首先，通过提供关于新型膜蛋白分子运作的发现边缘的基本信息，它将阐明细胞用必需氨基酸营养物质滋养自身的方式。其次，这个特殊的蛋白质家族不仅与健康的基本人体生理学密切相关，而且还与破坏性病理学密切相关，特别是需要 APC 转运蛋白向快速生长的恶性细胞提供氨基酸的各种癌症。