The functional organization of mammalian membranes

项目总结 我们的实验室研究哺乳动物膜的功能组织以产生机械性 深入了解脂质成分、膜结构和细胞生理学之间的联系。膜 主持所有细胞生物活动的主要部分，协调无数同时、并行的任务。这 哺乳动物脂体的显著复杂性和多样性使功能得以实现，这导致了 独特的生物物理表型组合，包括膜流动性、张力、曲率和侧向 分隔化。我们的目标是预见性地了解脂肪组学特征如何决定细胞膜。 特性，以及这些特性如何反过来调节细胞功能。实现这一目标的进展是由 高通量脂质组学、质膜生物物理分析、 和定量高分辨率光谱显微镜。利用这些，我们在以下方面取得了重大进展 了解哺乳动物膜的横向和横向组织的几个相互关联的方面。 我们已经定义了与有序膜结构域相关的蛋白质的广泛结构特征 以及这些结构域是如何参与膜交通的。尽管有这些见解，但仍然很少有 已知哪些蛋白质与膜结构域相关，以及为什么。我们的实验和计算 框架使我们能够解决关键的悬而未决的问题，包括：蛋白质的结构密码是什么 有序结构域的亲和力，以及蛋白质与膜结构域的结合如何促进其 本地化和功能？同时，我们也描述了哺乳动物非凡的可塑性 膜(特别是其对膳食脂肪酸的敏感性)，并表征了外部环境的影响 膜特性和细胞功能的输入。然而，细胞如何维持细胞膜的动态平衡 对来自饮食和其他外部输入的持续挑战的反应还不是很清楚。我们的 观察表明，对这种体内平衡机制的干扰可能提供一种新的治疗方法 心血管疾病或癌症的治疗策略。最后，我们最新的工作集中在 脂质在质膜双层的两个小叶之间的不对称分布。尽管这样 组成不对称似乎是生物膜的普遍设计原则，选择性 不对称带来的优势尚不为人所知。我们正在定义成分、生物物理和 哺乳动物细胞质膜的功能不对称性回答有关 膜不对称的生物物理后果和物理特性如何相互耦合 不对称的小叶。在功能上，耐人寻味的最新发现揭示了膜的瞬时丢失 非对称性在免疫激活过程中很普遍，是最佳反应所必需的；然而， 一过性脂质扰乱的潜在机制尚不清楚。回答这些问题 将促进我们对跨越生命之树的膜组织的功能作用的理解。

PROJECT SUMMARY Our laboratory investigates the functional organization of mammalian membranes to generate mechanistic insight into the connections between lipid composition, membrane structure, and cell physiology. Membranes host a major fraction of all cellular bioactivity, orchestrating myriad simultaneous, parallel tasks. This functionality is enabled by the remarkable complexity and diversity of mammalian lipidomes, which give rise to a unique combination of biophysical phenotypes, including membrane fluidity, tension, curvature, and lateral compartmentalization. We aim for a predictive understanding of how lipidomic features determine membrane properties, and how these in turn regulate cell functions. Progress towards this goal has been enabled by recent methodological advances in high-throughput lipidomics, biophysical analysis of plasma membranes, and quantitative high-resolution spectral microscopy. Using these, we have made significant advances in understanding several interrelated aspects of lateral and transverse organization of mammalian membranes. We have defined broad structural features responsible for protein association with ordered membrane domains and how such domains are involved in membrane traffic. Despite these insights, there remains remarkably little known about which proteins associate with membrane domains and why. Our experimental and computational framework allows us to address key outstanding questions, including: what are the structural codes for protein affinity for ordered domains, and how does protein association with membrane domains facilitate their localization and function? In parallel, we have characterized the remarkable plasticity of mammalian membranes (particularly their susceptibility to dietary fatty acids) and characterized the effects of external inputs on membrane properties and cell function. However, how cells maintain membrane homeostasis in response to continuous challenge from dietary and other external inputs is not well understood. Our observations suggest that interference with such homeostatic mechanisms may provide a novel therapeutic strategy for treatment of cardiovascular disease or cancer. Finally, our most recent work has focused on the asymmetric distribution of lipids between the two leaflets of the plasma membrane bilayer. Although such compositional asymmetry appears to be a universal design principle for living membranes, the selective advantages that asymmetry confers are not known. We are defining the compositional, biophysical, and functional asymmetry of the plasma membrane in mammalian cells to answer major open questions about the biophysical consequences of membrane asymmetry and how physical properties are coupled across asymmetric leaflets. Functionally, intriguing recent discoveries reveal that transient loss of membrane asymmetry is widespread during immune activation, and is necessary for optimal response; however, the mechanisms underlying these effects of transient lipid scrambling are unknown. Addressing these questions will advance our understanding of the functional role of membrane organization across the tree of life.