Structure and Function of Membrane Rafts

膜筏的结构和功能

• 批准号: 7029797
• 负责人: DEBORAH Ann BROWN
• 金额: $ 31.56万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7029797
• 关键词: biological signal transduction; caveolas; caveolins; cell component structure /function; cholesterol; endocytosis; fluorescence; gene expression; intermolecular interaction; lipid raft; mass spectrometry; membrane lipids; membrane proteins; membrane structure; protein binding; protein metabolism; protein structure function; protein transport; receptor expression; tissue /cell culture

DESCRIPTION (provided by applicant): 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 associate 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.

描述（由申请人提供）：脂质筏是有序阶段中存在的膜微域。这些在哺乳动物细胞中富含鞘脂和胆固醇。筏脂质与真核细胞的质膜中的其他脂质不一致，而是与它们作为单独的域共存。多种蛋白质可以分解为筏。最近的证据表明，许多在信号转导事件与筏相关的信号转导事件中重要的蛋白质，并且该关联对于它们的功能至关重要。小窝是脂质筏的特定子类。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直径约50-100 nm的定义质膜坑中。小窝被蛋白质外套所包围，其中蛋白质小窝蛋白-1是重要的成分。哺乳动物细胞中有三种小窝蛋白蛋白：Caveolins -1，-2和-3。小窝蛋白1和2通常共表达，而Caveolin-3仅限于肌肉细胞。小窝蛋白-2在没有小窝蛋白-1的情况下表达时，没有转运到细胞表面，无法制成小窝。但是，小窝蛋白1和2一起形成功能性小窝。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，以确定小窝蛋白-1如何与膜和筏子相互作用，以及它如何与膜胆固醇紧密结合，膜胆固醇是一种重要的木筏脂质。我们还将检查口腔在内吞作用中的作用，或从质膜中蛋白质和脂质内部化到细胞内部，并确定为什么此过程需要胆固醇。我们还将确定小窝如何在调节信号转导过程中发挥作用。值得注意的是，癌细胞中小窝蛋白-1蛋白的水平下降。由于Caveolae需要Caveolin-1形成，因此小窝通常也从这些细胞中消失。这表明，小窝在针对癌症的细胞防御中的重要功能。这种作用不可能是必不可少的，因为对于小鼠1完全不足并且没有小窝的小鼠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过程中起重要的备用作用，这在调节分解时可能导致癌症。