Collaborative Research: Arabidopsis 2010: Function/Structure Annotation of Lipid Binding Domains in Arabidopsis Thaliana Proteins: Computational Modeling of Subcellular Targeting

蛋白质与细胞膜的可逆结合是许多生物过程的核心，并且通常通过脂质相互作用蛋白质结构域来实现。拟南芥基因组包含至少2，000个这样的结构域。不同类型的脂质信号将结构域靶向不同的细胞膜。脂质结合结构域与膜表面的相互作用是其功能的重要组成部分。该项目的目的是在分子水平上了解这些结构域如何被招募到不同的细胞膜，以及蛋白质和脂质信号如何在膜表面横向组织，从而调节细胞过程。将通过综合计算和实验分析，在家族和基因组水平上确定功能。自动化高通量比较建模管道将检测拟南芥基因组中脂质结合结构域的新实例，并使用已知结构作为模板预测其氨基酸序列的结构。将计算这些模型的生物物理特性，并通过实验的解释和合理设计来测试功能预测。最终，详细的物理相互作用模型的基础脂质信号通路在膜表面将建立与实验合作。该项目反映了2010年项目的所有三个重点活动：1）基准基因功能。来自拟南芥的基因将与来自其他更多注释的模式生物的基因进行定量比较。2)开发用于分析基因功能的全基因组工具：高度模块化的比较建模管道是一个综合工具的框架，允许包含新的计算方法，以促进更大规模和更详细的基因功能注释。3)探索示例性网络和系统：将利用单个脂质结合结构域的结果来建模蛋白质和脂质如何协作来转导细胞信号传导。最后，将实施一种自动化机制，提醒其他2010年计划组注意潜在的有用结果。关于这个项目的信息发布在http://maat.med.cornell.edu/Arabidopsis2010/arabidopsis2010.html.The这项工作的基础是康奈尔大学威尔医学院（WMC）和纽约城市大学布鲁克林学院（CB）之间的强大合作伙伴关系，这是一个非博士学位授予机构。这种伙伴关系的价值在于研究、教育、指导和外联活动。通过该项目，两名职业生涯初期的女科学家（其中一人有两个孩子）将接受生物学和计算新领域的培训，并将通过该项目和其他研究领域共同为妇女创造一个有利的研究环境。这两个实验室都为许多年轻女性提供了从高中到博士后的各级教育的指导。多学科和多民族学生的参与很强：两名少数民族女高中生进入了国际英特尔竞赛的决赛，另一名少数民族女高中生目前正在从事英特尔的一个项目。CB和WMC的本科生和研究生正在通过参与该项目和正式课程工作进行计算生物学培训。两名研究人员都设计和教授生物信息学，计算生物学，生物化学，逻辑和批判性分析以及基于期刊的“焦点小组”课程。该项目的成果将通过以下方式广泛传播：1）一个专门的、公众可访问的、数据库驱动的网站，该网站与在线拟南芥资源相链接; 2）参加多学科会议和拟南芥特定的数据支持服务; 3）在高质量的多学科期刊上发表文章，例如PLoS Computational Biology，该期刊旨在使生物学家能够使用计算;和4）为“科学界的妇女”方案和旨在从其他领域招收生物学学生的方案举办的研讨会，例如美国物理学会生物学补习班。预计，一个非常成功的，八届会议，48发言人的蛋白质/膜相互作用的研讨会，由美国化学学会2006年3月会议的研究人员之一组织，是第一次在一系列类似的会议，将汇集实验和计算研究人员在这一领域。未来的会议将专门讨论拟南芥膜结合蛋白。

The reversible binding of proteins to cellular membranes is central to many biological processes and is often accomplished through lipid-interacting protein domains. The Arabidopsis genome contains at least 2,000 such domains. Different types of lipid signals target the domains to different cellular membranes. The interaction of lipid-binding domains with membrane surfaces is an essential part of their function. This project aims to understand, at the molecular level, how these domains are recruited to different cellular membranes and how proteins and lipid signals are organized laterally at membrane surfaces and, thus, regulate cellular processes. Function will be determined at the family and genome levels through the synthesis of computational and experimental analyses. An automated high-throughput comparative modeling pipeline will detect new instances of lipid-binding domains in the Arabidopsis genome and predict the structures of their amino acid sequences using known structures as templates. The biophysical properties of these models will be calculated and the functional predictions will be tested through the interpretation and rational design of experiments. Ultimately, detailed models of the physical interactions underlying lipid signaling pathways at membrane surfaces will be built in collaboration with experiment. This project reflects all three of the current 2010 Project focus activities: 1) Benchmarking gene function. Genes from Arabidopsis will be quantitatively compared with genes from other, much more annotated model organisms. 2) Developing genome-wide tools for analyzing gene function: The comparative modeling pipeline, which is highly modular, is the framework for a comprehensive tool that allows for the inclusion of new computational methods to facilitate both larger scale and more detailed annotation of gene function. 3) Exploring exemplary networks and systems: The results for individual lipid-binding domains will be leveraged to model how proteins and lipids collaborate to transduce cellular signaling. Finally, an automated mechanism for alerting other 2010 Program groups to potentially useful results will be implemented. Information on this project is posted at http://maat.med.cornell.edu/Arabidopsis2010/arabidopsis2010.html.The foundation of this effort is a strong partnership between Weill Medical College of Cornell University (WMC) and City University of New York Brooklyn College (CB), which is a non-PhD granting institution. The values of this partnership are research, education, mentoring, and outreach activities. Through this project, two early career female scientists, one of which has two children, will receive training in new areas of biology and computation and, together, will develop a supportive research environment for women through this project as well as other areas of research. Both labs mentor many young women at all levels of education, from high school through the postdoctoral level. There is strong multidisciplinary and multiethnic student participation: Two minority female high school students were finalists in the International Intel Competition, and another minority female high school student is currently working on an Intel project. Undergraduate and graduate students at CB and WMC are being trained in computational biology by participating in this project and through formal course work. Both investigators design and teach classes in Bioinformatics, Computational Biology, Biochemistry, Logic and Critical Analysis, and journal-based "Focus Groups". The results of this project will be broadly disseminated through 1) a dedicated, publicly accessible, database-driven website with links to online Arabidopsis resources; 2) participation in multi-disciplinary conferences and Arabidopsis-specific data-support services; 3) publications in quality, multidisciplinary journals, e.g. PLoS Computational Biology, which seeks to make computation accessible to biologists; and 4) seminars presented to "Women in Science" programs and programs meant to recruit students from other fields into biology, e.g. American Physical Society Biology Tutorials. It is anticipated that a highly successful, eight-session, 48-speaker symposium on protein/membrane interactions, organized by one of the investigators for the American Chemical Society March 2006 meeting, is the first in a series of similar meetings that will bring together experimental and computational researchers in this field. Future meetings will have sessions devoted to Arabidopsis membrane binding proteins.