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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：
10004656
负责人：
MATTHIAS BUCK
金额：
$ 44.7万
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004656
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 Epithelium 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.

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