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Structure and function of plexin - co-receptor interactions

丛蛋白-共受体相互作用的结构和功能

基本信息

批准号：
10246388
负责人：
MATTHIAS BUCK
金额：
$ 43.35万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10246388
关键词：
Address Affect Age related macular degeneration Antibodies Axon Binding Binding Proteins Biological Assay Biological Models Blindness Blood Vessels Cell Adhesion Cell Adhesion Molecules Cell Line Cell membrane Cells Cellular Membrane Cellular Structures Cellular biology Collaborations Complex Computer Models Cues Data Dendrites Development Diabetic Retinopathy Disease ERBB2 gene Endothelium Environment Epithelial Epithelial Cells Extracellular Domain Eye Eye diseases Eyedrops FDA approved Family Fluorescence Resonance Energy Transfer Fluorescence Spectroscopy Future Guanosine Triphosphate Phosphohydrolases Homo Human Integral Membrane Protein Intravenous KDR gene Knowledge Ligands Lipid Bilayers Lipid Binding Lipids Lucentis Maintenance Measures Membrane Membrane Lipids Membrane Proteins Modeling Molecular Monoclonal Antibodies Monomeric GTP-Binding Proteins Mutation Natural regeneration Nerve Neurons Neuropilin-1 Neuropilins Optic Nerve Oral Outcome Pathologic Neovascularization Pathway interactions Patients Peptides Phosphatidylinositol 4,5-Diphosphate Play Protein Region Proteins Receptor Cell Receptor Signaling Regulation Resistance Retina Retinal Diseases Role Route Semaphorins Signal Transduction Specificity Structure Structure of retinal pigment epithelium Swelling System Techniques Testing Therapeutic Therapeutic Effect Time Transmembrane Domain United States Vascular Endothelial Growth Factors Vascularization Visual Acuity Work angiogenesis antiangiogenesis therapy antitumor agent base biochemical tools biophysical tools blood vessel development cancer therapy cell behavior cell motility cell type computer studies design diagnostic biomarker experimental study inhibitor/antagonist interdisciplinary approach macular edema membrane model molecular dynamics neuron development novel older patient peptide drug plexin preclinical trial protein protein interaction ranibizumab receptor reconstitution rho rho GTP-Binding Proteins small molecule structural biology synergism targeted treatment therapeutic development time use tool tumor progression

项目摘要

Modified Project Summary/Abstract Plexins are transmembrane receptors that make cell guidance decisions in vascular and neuronal development, disease, and regeneration. Targeting plexins and their co-receptors, especially neuropilin, is a novel route to treating retinal diseases such as age-related macular degeneration (AMD) and diabetic retinopathy, but the mechanistic details of plexin activation are poorly understood. We will characterize the interactions between plexin and membrane lipids. Plexins are unique transmembrane receptors in that their intracellular regions interact directly with membrane-anchored small GTPases. These Ras and Rhofamily GTPases, in turn, are associated with cell migration in the retina. The preliminary results in aim 1 indicate that protein-membrane interactions play a key role in the signaling mechanisms of plexins, for example, rationalizing the different functional roles of the GTPases in the system. Our work will be the first to study the interactions of plexin domains with the lipid bilayer at the molecular level. This includes, in aim1, the plexin-B1 transmembrane region which has been predicted to assume three states of inter helix contacts. Altogether the results support a multi-state model which incorporates previous and the new results, but also points to critical new interactions between the proteins and the lipid bilayer. Aim 2 seeks to resolve the structure and function of the transmembrane regions of plexin coreceptors, neuropilin and semaphorins. We hypothesize that such interactions set up cross signaling with ligands and co-receptors. In order to address this hypothesis, we will examine receptor homo- and hetero-oligomerization using time resolved fluorescence spectroscopy and functional experiments, both using live cells. Together with NMR and molecular dynamics, these complementary tools will address the hypothesis at different levels of complexity, ranging from domain level to in-cell behavior. Plexin function is modulated by interaction with co-receptors, such as neuropilins which are also single pass transmembrane (TM) proteins. TM regions are recently recognized as an effective target for peptides designed to disrupt receptor signaling. In aim 2, we will characterize the structure and function of plexin TM interactions with the TM domains of neuropilins. Our data suggest that TM interactions between plexins and certain of their semaphorin ligands can also occur in cis. Such TM based regulation would be a novel mechanism in the plexin field, and one that can be targeted to inhibit the receptors in the retina. Specifically, expanding the successful use of neuropilin peptides as anti-tumor agents, TM regions are a target for anti-angiogenesis therapy in eye disease such as AMD and diabetic retinopathy.

修改后的项目摘要/摘要丛蛋白是跨膜受体，在血管和神经元发育、疾病和再生中做出细胞指导决定。靶向丛蛋白及其共受体，特别是神经纤毛蛋白，是治疗视网膜疾病如年龄相关性黄斑变性（AMD）和糖尿病视网膜病变的新途径，但丛蛋白激活的机制细节知之甚少。我们将描述丛蛋白和膜脂质之间的相互作用。丛蛋白是独特的跨膜受体，因为它们的细胞内区域直接与膜锚定的小GTP酶相互作用。这些Ras和Rhofamily GTP酶又与视网膜中的细胞迁移相关。目的1中的初步结果表明，蛋白质-膜相互作用在丛蛋白的信号传导机制中起关键作用，例如，合理化系统中GTP酶的不同功能作用。我们的工作将是第一个在分子水平上研究丛蛋白结构域与脂质双层的相互作用。这包括，在aim 1，plexin-B1跨膜区已被预测为假设三种状态的螺旋间接触。总之，这些结果支持一个多状态模型，它结合了以前的和新的结果，但也指出了关键的蛋白质和脂质双层之间的新的相互作用。目的二是研究丛蛋白协同受体、神经毡蛋白和脑信号蛋白跨膜区的结构和功能。我们假设这种相互作用与配体和共受体建立了交叉信号。为了解决这一假设，我们将研究受体同源和异源寡聚化使用时间分辨荧光光谱和功能实验，都使用活细胞。与NMR和分子动力学一起，这些互补的工具将在不同的复杂程度上解决这个假设，从结构域水平到细胞内行为。丛状蛋白功能通过与共受体（例如也是单次跨膜（TM）蛋白的神经纤毛蛋白）的相互作用来调节。TM区域最近被认为是设计用于破坏受体信号传导的肽的有效靶标。在目标2中，我们将表征丛蛋白TM与神经纤毛蛋白TM结构域相互作用的结构和功能。我们的数据表明，TM之间的相互作用，丛蛋白和它们的某些semaphorin配体也可以发生顺式。这种基于TM的调节将是丛蛋白领域中的一种新机制，并且可以靶向抑制视网膜中的受体。具体地，扩展了神经纤毛蛋白肽作为抗肿瘤剂的成功用途，TM区域是在诸如AMD和糖尿病视网膜病变的眼部疾病中抗血管生成疗法的靶标。