Structural Diversity of Caveolins

Caveolins 的结构多样性

• 批准号: 10729179
• 负责人: Anne K Kenworthy
• 金额: $ 49.17万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10729179
• 关键词: Address; Binding; Biochemical; Biochemistry; Biogenesis; Biological; Cardiovascular Diseases; Caveolae; Caveolins; Cell membrane; Cell physiology; Cells; Cellular biology; Complement; Complex; Computer Analysis; Cryoelectron Microscopy; Cytoplasm; Defect; Development; Disease; Electron Microscopy; Elements; Ensure; Evolution; Face; Family; Gene Family; Genetic; Human; In Vitro; Integral Membrane Protein; Knowledge; Link; Lipids; Lipodystrophy; Malignant Neoplasms; Maps; Membrane; Membrane Proteins; Modeling; Mutation; Organism; Pathogenicity; Physiological; Physiological Processes; Physiology; Play; Predisposition; Process; Property; Protein Family; Proteins; Protomer; Recording of previous events; Refractory; Resolution; Role; Rotation; Series; Shapes; Sister; Structural Protein; Structure; Surface; Testing; Variant; Vertebrates; body system; caveolin 1; cell type; density; design; flasks; insight; member; mouse model; particle; protein function; protein structure; success; three dimensional structure

Flask shaped invaginations known as caveolae function as important regulators of cellular and physiological processes and have been linked to a number of diseases ranging from cardiovascular disorders to cancer. The caveolins, a family of monotopic membrane proteins, serve as fundamental building blocks of caveolae. Remarkably, caveolins have eluded high resolution characterization since their discovery in the early 1990s. This has made it nearly impossible to understand the exact mechanisms by which caveolae form and function or how defects in caveolae give rise to disease. To fill this critical gap in knowledge, we have assembled an investigative team consisting of experts in single particle electron microscopy, the structure of membrane proteins, computational analysis of protein structure, and the cell biology and biochemistry of caveolins. Our combined efforts have now led to the first atomic structure of human caveolin-1 (Cav1) assembled in an oligomeric form required for caveolae assembly, the 8S complex. This represents an enormous step forward for the field, which up until now has operated in the absence of definitive structural insights into how Cav1 oligomerize to form complexes or what regions of Cav1 are required to bind other proteins and lipids to build functional caveolae. Here, we propose to leverage our success in determining the structure of the Cav1 8S complexes to address a new series of questions about the structural and functional properties of this enigmatic protein family using a combination of structural, computational, biochemical, and cell biological approaches. First, we will interrogate the role of key residues and domains in controlling the formation and structure of human caveolin 8S complexes and its sensitivity to naturally occurring pathogenic mutations. Second, we will test the hypothesis that the ability of caveolins to assemble into membrane-associated oligomeric complexes capable of remodeling membranes is one of their most ancient functions by studying representative caveolins across the evolution. Third, we will probe the ability of structurally diverse caveolins, generated either as a consequence of genetic variability or evolutionary divergence, to support the biogenesis of functional caveolae. Successful completion of these studies will provide a much-needed framework to understand how Cav1 assembles into caveolae capable of ensuring proper function of multiple cell types and organ systems, how disease-associated mutations of Cav1 interfere with these processes in humans, and how evolution has harnessed this protein to accomplish its many roles in organisms across Metazoa and beyond.

称为小窝的瓶状内陷作为细胞和生理的重要调节因子发挥作用。 它与许多疾病有关，从心血管疾病到癌症。 小窝蛋白是一个单调的膜蛋白家族，是小窝的基本组成部分。 值得注意的是，窖蛋白自20世纪90年代初被发现以来一直没有得到高分辨率的表征。 这使得人们几乎不可能理解小窝形成和功能的确切机制 或小窝的缺陷如何导致疾病。为了填补这一关键的知识空白，我们收集了一份 由单粒子电子显微镜专家组成的调查小组， 蛋白质，蛋白质结构的计算分析，以及小窝蛋白的细胞生物学和生物化学。我们 联合努力现在已经导致了人类小窝蛋白-1（Cav 1）的第一个原子结构组装在一个 小窝组装所需的低聚形式，即8 S复合物。这代表着一个巨大的进步 到目前为止，该领域一直在缺乏明确的结构见解的情况下运作， 寡聚化形成复合物或Cav 1的哪些区域需要结合其他蛋白质和脂质来构建 功能性小窝在这里，我们建议利用我们在确定Cav 1 8 S结构方面的成功 复合物，以解决一系列新的问题的结构和功能特性，这一谜 使用结构、计算、生物化学和细胞生物学方法的组合来分析蛋白质家族。 首先，我们将询问关键残基和结构域在控制蛋白质的形成和结构中的作用。 人小窝蛋白8 S复合物及其对自然发生的致病突变的敏感性。二是 检验小凹蛋白组装成膜相关寡聚复合物的能力 通过研究具有代表性的小窝蛋白， 在进化过程中。第三，我们将探索结构多样的小凹的能力，这些小凹要么是作为 遗传变异或进化分歧的结果，以支持功能性小窝的生物起源。 这些研究的成功完成将提供一个急需的框架，以了解Cav 1 组装成能够确保多种细胞类型和器官系统正常功能的小窝， Cav 1的疾病相关突变干扰了人类的这些过程，以及进化是如何影响 利用这种蛋白质来完成它在后生动物和其他生物体中的许多作用。