FASEB Conference: Lipid Modifications of Proteins to be held on August 6-11, 2000 in Copper Mountain, CO

本项目为美国实验生物学学会联合会（FASEB）将于2000年8月6日至8月11日在科罗拉多州铜山举行的“蛋白质脂质修饰”会议寻求部分支持。这将是对真核细胞中蛋白质脂质修饰的三种主要形式——酰化、前酰化和gpi锚定的结构和功能的最新探索，并将为这些独立但相关领域的工作者提供一个独特的机会来交流思想和见解。蛋白质的脂质修饰是一个非常活跃的领域。在过去的几年里，这一领域的研究重点已经从早期关注脂质修饰蛋白的鉴定和结构研究扩展到包括对脂质组生理作用的阐明。会议的主要主题概述如下。信号。令人惊讶的是，高比例的脂质相关蛋白是细胞信号传导途径的关键参与者。这些包括Ras、src家族酪氨酸激酶、异源三聚体G蛋白和7-跨膜激素受体。在几乎所有的情况下，脂质修饰是功能所必需的。这将注意力集中在这些脂质组在细胞生理学中的特定作用上。所有脂质修饰都能使亲水性蛋白与膜结合。为什么会有不同的脂质修饰？它们有什么共同点，又有什么不同？最近对Ras的研究结果表明，用不同的脂质修饰同一蛋白可以显著改变其功能。对这些问题和其他问题的新见解可以通过关注个人变化的人们之间的讨论得到最好的回答。这是本次会议最重要的目标之一。膜筏。GPI锚定和酰化的一个重要功能是将蛋白质靶向到胆固醇和富含鞘脂的膜结构域或筏上。许多细胞信号事件发生在这些区域的发现是过去两年来令人兴奋的发展，并引起了极大的兴趣。筏的结构和功能，以及其中的脂质连接蛋白的功能，是会议的另一个主题。与这一主题相关的是胆固醇在膜筏的生物发生和维持中的重要性，以及最近发现的胆固醇作为细胞表面信号分子刺猬蛋白翻译后修饰的作用。抑制脂质修饰的治疗应用。本次会议的第三个主题将探讨抑制脂质修饰如何作为对抗疾病的高效策略。这项工作可以分为两个主要子类。第一种是使用法尼基转移酶抑制剂来钝化活化Ras的功能。第二个目标是由单细胞真核病原体引起的传染病，如锥虫、利什曼原虫和疟原虫。这些生物大多表达了极高水平的gpi锚定蛋白。通过多步骤途径合成这些复杂结构需要许多酶，其中一些酶是病原体特有的，不为哺乳动物宿主所共有。这些都是药物设计的关键目标，这是一个正在积极追求的途径。肉豆蔻酰化和戊烯酰化的病原体特异性特征也同样被靶向。脂质修饰和膜靶向。所有的脂质修饰都增加了蛋白质的疏水性，并且所有的脂质修饰都可以将脂化蛋白靶向到膜上。但是脂化蛋白是如何针对不同的膜的呢？酰基化和戊基化蛋白的特异性膜靶向是当前研究最活跃的领域之一。我们将探索酰基化和戊基化蛋白质在合成后可以通过细胞遵循复杂的途径。脂质修饰蛋白在信号转导、膜和蛋白质运输、细胞增殖和分化等细胞过程中起着不可或缺的作用。细胞生物学、遗传学、生物化学和生物物理学的学科都被用来理解蛋白质脂化的生物学。这次会议提供了一个机会，将从这些方法中获得的信息整合到一个更连贯的关于脂质修饰如何促进蛋白质功能的图景中。

This project seeks partial support for the Federation of American Societies of Experimental Biology (FASEB) conference on "Lipid Modifications of Proteins" to be held from August 6 to August 11, 2000 at Copper Mountain, Colorado. This will be a state-of-the-art exploration of the structure and function of acylation, prenylation, and GPI-anchorage, the three major forms of lipid modification of proteins in eukaryotic cells, and will provide a unique opportunity for workers in these separate but related fields to exchange ideas and insights. Lipid modification of proteins is an extremely active field. The focus of research in this area has broadened in the past few years from an earlier focus on identification of lipid-modified proteins and structural studies, to include elucidation of the physiological role of the lipid group. Outlined below are the major themes of the meeting. Signaling. Surprisingly high proportions of lipid-linked proteins are key players in cellular signaling pathways. These include Ras, Src-family tyrosine kinases, heterotrimeric G proteins, and 7- transmembrane spanning hormone receptors. In virtually all cases, the lipid modifications are required for function. This focuses attention on the specific role of these lipid groups in cellular physiology. All lipid modifications can allow association of otherwise hydrophilic proteins with membranes. Why are there different lipid modifications? What do they have in common, and how do they differ? Recent results on Ras show that modification of the same protein with different lipids can substantially alter function. New insights into these and other questions can be best answered by discussion between people who focus on individual modifications. This is one of the most important goals of this meeting. Membrane rafts. An important function of both GPI anchorage and acylation is to target proteins to cholesterol and sphingolipid-rich membrane domains or rafts. The finding that a number of cellular signaling events occur in these domains is an exciting development of the past two years, and has attracted a great deal of interest. Structure and function of rafts, and function of lipid-linked proteins in them, is another theme of the conference. Related to this theme are the importance of cholesterol in the biogenesis and maintenance of membrane rafts and its recently discovered role as a post-translational modification of the cell surface signaling molecule, hedgehog. Therapeutic applications of inhibiting lipid modifications. A third theme of this meeting will explore how inhibition of lipid modification can be used as a highly effective strategy in fighting disease. This effort can be divided in two major subclasses. The first is the use of farnesyl transferase inhibitors to blunt the function of activated Ras. The second target is infectious disease caused by unicellular eukaryotic pathogens such as Trypanosoma, Leishmania, and Plasmodium. Most of these organisms express extremely high levels of GPI-anchored proteins. Synthesis of these complex structures by a multistep pathway requires a number of enzymes, some of which are specific to the pathogens and are not shared by mammalian hosts. These are key targets for drug design, an avenue that is being actively pursued. Pathogen-specific features of myristoylation and prenylation are being targeted similarly. Lipid modification and membrane targeting. All lipid modifications increase protein hydrophobicity, and all lipid modifications can target lipidated proteins to membranes. But how are lipidated proteins targeted to different membranes? The specificity of membrane targeting of acylated and prenylated proteins is one of the most active areas of current research. The emerging picture that acylated and prenylated proteins can follow complicated pathways through cells following synthesis will be explored. Lipid-modified proteins are integral players in the cellular processes of signal transduction, membrane and protein trafficking, cellular proliferation and differentiation. The disciplines of cell biology, genetics, biochemistry, and biophysics are all used to understand the biology of protein lipidation. This meeting provides the opportunity to integrate the information derived from these approaches into a more coherent picture of how lipid modifications contribute to protein function.