Structure and Function of Membrane Rafts

膜筏的结构和功能

基本信息

批准号：
7589797
负责人：
DEBORAH Ann BROWN
金额：
$ 30.74万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-09-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7589797
关键词：
Affect Affinity Aftercare Back Binding Biochemical Biological Biological Assay Breast Cancer Cell C-terminal COS-1 Cells Caliber Capsid Proteins Caveolae Caveolins Cell membrane Cell physiology Cell surface Cells Chloroquine Cholesterol Clathrin Collaborations Cyclodextrins Cytoplasmic Tail Dependence Detergents ERBB2 gene Endocytosis Eukaryotic Cell Event Excision Fatty Alcohols Fluorescence Foundations Geldanamycin Goals Human In Vitro Label Lead Lipids London Malignant Neoplasms Mammalian Cell Maps Measures Mediating Membrane Membrane Microdomains Membrane Structure and Function Methods Molecular Conformation Mus Muscle Cells Pathway interactions Peptides Phase Play Positioning Attribute Process Proteins Regulation Research Personnel Rest Role Signal Transduction Simian virus 40 Site Solid Sphingolipids Sterols Stream Structural Protein Structure System Tertiary Protein Structure Testing Work analog base cancer cell caveolin 1 caveolin-2 caveolin-3 in vivo membrane model mutant novel overexpression research study tool trafficking tumor

项目摘要

Lipid rafts are membrane microdomains present in an ordered phase. These are rich in sphingolipids and cholesterol in mammalian cells. Raft lipids do not mix uniformly with other lipids in the plasma membranes of eukaryotic cells, but instead co-exist with them as separate domains. A variety of proteins can partition into rafts. Recent evidence shows that many proteins important in signal transduction events assocaite with rafts, and that this association can be essential for their function. Caveolae are a specific subclass of lipid raft. Caveolae are a specific subclass of lipid raft. Here, the specialized raft lipid mixture is concentrated in defined plasma membrane pits, of about 50-100 nm in diameter. Caveolae are surrounded by a protein coat, of which the protein caveolin-1 is an important component. There are three caveolin proteins in mammalian cells: caveolins-1, -2, and -3. Caveolins 1 and 2 are usually co-expressed, while caveolin-3 is restricted to muscle cells. Caveolin-2, when expressed in the absence of caveolin-1, is not transported to the cell surface, and can not make caveolae. However, caveolins 1 and 2 together can form functional caveolae. We will examine purified caveolin-1 and artificial caveolin-1 peptides in model membranes, to determine how caveolin-1 interacts with membranes and with rafts, and how it binds tightly to membrane cholesterol, an important raft lipid. We will also examine the role of caveolae in endocytosis, or internalization of proteins and lipids from the plasma membrane into the cell interior, and determine why cholesterol is required for this process. We will also determine how caveolae may play a role in regulating signal transduction processes. Remarkably, levels of caveolin-1 protein decline in cancer cells. As caveolae require caveolin-1 to form, caveolae generally disappear from these cells as well. This points to an important function of caveolae in cellular defenses against cancer. This role cannot be essential, as mice that are completely deficient for caveolin-1, and have no caveolae, are not particularly susceptible to tumors. Nevertheless, caveolae are likely to play an important back-up role in regulating cellular signal transduction processes, which can lead to cancer when regulation breaks down.

脂质筏是在有序相中存在的膜微区。这些富含鞘脂，哺乳动物细胞中的胆固醇。筏脂质不会与其他脂质均匀混合真核细胞，而是将其作为单独的域共存。各种蛋白质可以分配到筏。最近的证据表明，许多蛋白质在信号转导事件中很重要木筏，这种关联对于它们的功能至关重要。小窝是脂质的特定子类筏。小窝是脂质筏的特定子类。在这里，专门的筏脂质混合物集中在定义的质膜坑，直径约为50-100 nm。小窝被蛋白质包围涂层，其中蛋白质口腔1是重要组成部分。有三种小窝蛋白蛋白哺乳动物细胞：Caveolins -1，-2和-3。小窝蛋白1和2通常共表达，而Caveolin-3为仅限于肌肉细胞。小窝林-2在没有小窝蛋白-1的情况下表达时，未传输到细胞表面，无法制作小窝。但是，小窝蛋白1和2一起形成功能小屋。我们将在模型膜中检查纯化的小窝蛋白-1和人造小窝蛋白-1肽确定小窝蛋白-1如何与膜和筏子相互作用，以及它如何与膜紧密结合胆固醇，一种重要的木筏脂质。我们还将检查小窝在内吞作用中的作用，或蛋白质和脂质从质膜内部化到细胞内部，并确定为什么此过程需要胆固醇。我们还将确定小屋如何在调节中发挥作用信号转导过程。值得注意的是，癌细胞中小窝蛋白-1蛋白的水平下降。作为小屋需要Caveolin-1形成，Caveolae通常也从这些细胞中消失。这表明了一个重要的小窝在针对癌症的细胞防御中的功能。这个角色不是必需的，因为老鼠是对于小窝蛋白1的完全不足，没有口腔，并不特别容易受到肿瘤的影响。然而，小窝可能在调节细胞信号转导中起重要的备份作用过程，当调节分解时可能导致癌症。