Molecular Mechanisms of Active Transport Across Cellular Membranes

跨细胞膜主动运输的分子机制

基本信息

批准号：
8119138
负责人：
Emad Tajkhorshid
金额：
$ 29.83万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-17 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8119138
关键词：
ATP Hydrolysis ATP-Binding Cassette Transporters Active Biological Transport Adenine Nucleotide Translocase Area Binding Biomedical Research Carrier Proteins Cells Cellular Membrane Chemicals Complex Computer Hardware Computer software Coupled Coupling Cytoplasm Data Discipline Energy-Generating Resources Event Family Glutamate Transporter Health Hormones Human Hydrolysis Inner mitochondrial membrane Investigation Ions Life Maltose Mechanics Mediating Membrane Membrane Potentials Membrane Transport Proteins Methods Mitochondria Modeling Molecular Molecular Machines Nature Neurotransmitters Nucleotides Nutrient Pathway interactions Periplasmic Binding Proteins Physiology Positioning Attribute Process Proteins Protons Research Resolution Specificity Structure System base biological research human disease meetings member molecular dynamics neurotransmitter uptake pH gradient permease protein complex simulation

项目摘要

DESCRIPTION (provided by applicant): Membrane transporters are principal players in active exchange of materials across the cellular membrane, one of the most fundamental and highly regulated processes in living cells. Investigating the molecular basis of their function, therefore, is of utmost importance in various disciplines of biological and biomedical research. These complex proteins provide highly sophisticated, operationally fine-tuned molecular machines to efficiently couple various sources of energy in the cell to vectorial translocation of various molecular species across the membrane against their chemical gradient. Investigation of the molecular details of the mechanism of membrane transporters poses a major challenge, primarily due to their structural complexity and the high dimensionality of the process of energy-dependent transport furnished by them. Substrate binding and translocation along the permeation pathway in membrane transporters is closely coupled to numerous stepwise protein conformational changes of various magnitudes that are induced and/or coordinated by the energy- providing mechanisms, e.g., binding and co-transport of protons and other ions, or binding and hydrolysis of ATP. A detailed description of the mechanism of transport in membrane transporters, therefore, relies on methods that can describe the dynamics of these processes at an atomic level. Molecular dynamics simulation remains a highly relevant approach with sufficient temporal and spatial resolutions to investigate such processes. Application of the method to membrane transporters is a very young area of research, since sufficient structural data required for such simulations has become available only recently. Furthermore, in order to describe biologically relevant events and steps involved in the function of membrane transporters, atomistic simulations of these large biomolecules on the orders of at least 0.1-1 <s are required, a computational demand which has also been met only recently. Though still extremely challenging, owing to the timely convergence of discoveries of membrane transporter structures and advances in computer hardware and software, we are now in an unprecedented position to expand the scope of simulation studies into the realm of membrane transporters and investigate the molecular basis of their function. In this application, we propose projects investigating three active membrane transporters: (1) Maltose transporter, an ABC transporter in which ATP binding and hydrolysis drive the process of substrate transport; (2) Glutamate transporter (GluT), representing secondary transporters that use the ionic gradient across the membrane as the source of energy for their function; and (3) the mitochondrial ADP/ATP carrier (AAC) which relies on the membrane potential for exchange of nucleotides betwee the cytoplasm and the mitochondria. PUBLIC HEALTH RELEVANCE: Membrane transporters are proteins that mediate selective transport of a wide range of materials, e.g., nutrients, hormones, and neurotransmitters, across the cellular membrane. They are essential to almost all aspects of human physiology, and their malfunction is associated with a large number of human diseases. The research proposed in this application will investigate the mechanism of function of several membrane transporters at a molecular level.

描述（由申请人提供）：膜转运蛋白是跨细胞膜物质主动交换的主要参与者，这是活细胞中最基本且高度调控的过程之一。因此，研究其功能的分子基础在生物学和生物医学研究的各个学科中至关重要。这些复杂的蛋白质提供了高度复杂、可操作微调的分子机器，可以有效地将细胞中的各种能量源与各种分子物种相对于其化学梯度跨膜的矢量易位耦合。对膜转运蛋白机制的分子细节的研究提出了重大挑战，这主要是由于它们的结构复杂性和它们提供的能量依赖性转运过程的高维性。膜转运蛋白中沿渗透途径的底物结合和易位与许多不同程度的逐步蛋白质构象变化密切相关，这些变化是由能量提供机制诱导和/或协调的，例如质子和其他离子的结合和共转运，或 ATP 的结合和水解。因此，对膜转运蛋白转运机制的详细描述依赖于能够在原子水平上描述这些过程的动力学的方法。分子动力学模拟仍然是一种高度相关的方法，具有足够的时间和空间分辨率来研究此类过程。该方法在膜转运蛋白上的应用是一个非常年轻的研究领域，因为此类模拟所需的足够的结构数据直到最近才可用。此外，为了描述膜转运蛋白功能中涉及的生物相关事件和步骤，需要对这些大生物分子进行至少0.1-1<s量级的原子模拟，这一计算需求最近才得到满足。尽管仍然极具挑战性，但由于膜转运蛋白结构的发现以及计算机硬件和软件的进步的及时融合，我们现在处于前所未有的位置，可以将模拟研究范围扩展到膜转运蛋白领域并研究其分子基础。他们的功能。在此应用中，我们提出了研究三种活性膜转运蛋白的项目：（1）麦芽糖转运蛋白，一种 ABC 转运蛋白，其中 ATP 结合和水解驱动底物转运过程； (2) 谷氨酸转运蛋白 (GluT)，代表利用跨膜离子梯度作为其功能能量来源的二级转运蛋白； (3)线粒体ADP/ATP载体(AAC)，其依赖于膜电位在细胞质和线粒体之间交换核苷酸。公共卫生相关性：膜转运蛋白是介导多种物质（例如营养素、激素和神经递质）跨细胞膜选择性转运的蛋白质。它们对人类生理学的几乎所有方面都至关重要，它们的功能障碍与大量人类疾病有关。本申请提出的研究将在分子水平上研究几种膜转运蛋白的功能机制。