CAREER: Bioinformatics of Protein Post-Translational Modifications

印第安纳大学因PreDrag Radivojac开发研究蛋白质翻译后修饰(PTM)的新方法而获得职业奖，即翻译后对蛋白质结构的共价修饰。现已知道，在真核生物中，有200多种PTM类型通过作为分子开关来调节蛋白质的活性，这些开关可以开启和关闭蛋白质功能，稳定蛋白质或将其作为破坏的目标，或确定其细胞位置。本研究的目的是开展以下研究活动：(1)开发PTM位点的自动标注模型(Aim 2)分析PTM位点的结构和功能特性(Aim 3)结合蛋白质生物信息学和蛋白质组学构建PTM的所有主要智力优点的功能图谱。该项目介绍了一种新的整合蛋白质生物信息学和蛋白质组学的框架，以全面了解PTMS的调节和信号作用。除了新的生物学知识外，该项目还将开发一套工具，使蛋白质组学分析准确有效，并帮助实验生物学家进行实验设计。组合爆炸是目前蛋白质组学研究PTM及其参与的细胞过程的主要障碍。因此，建议通过结合PTM预测来确定蛋白质组学搜索的优先顺序不仅将使此类研究变得现实，而且还将通过减少有效数据库大小来识别许多新的位点。PTM经常发生在非结构蛋白质区域，这些区域不容易用传统的实验方法(X射线结晶学、核磁共振光谱)和结构生物信息学来研究。发展基于序列的预测PTM位点的方法，将它们整合到蛋白质组研究中进行验证，并调查PTM与基因数据之间的关系，可能对于理解许多疾病的分子基础，从而促进药物设计和临床治疗至关重要。只有通过研究和跨学科教育的整合，才能实现在分子水平上理解生命和推进医学研究的深远承诺。为了实现这一目标，PI将扩展和开发研究生和本科生的新课程，让学生接受先进的教育，并通过积极、严格和热情的学习环境，培养一代有能力进一步发展的新专家和研究人员。教材和研究成果将通过我们的网站、在国际公认的期刊上发表论文和参加主要会议来传播。该项目的教育计划将通过与印第安纳大学战略指导办公室(OSM)和研究生和教授计划联盟(AGEP)合作，确保代表不足的少数群体和社会经济群体参与研究。该计划的两个重要组成部分是：(I)通过OSM/AGEP以及涉及数据挖掘和生物信息学的课程吸引代表性不足的学生，以及(Ii)通过承诺提供资金、咨询和辅导来留住和提升代表性不足的学生。

Indiana University is given a CAREER award for Predrag Radivojac to develop new methods to study protein post-translational modifications (PTMs), i.e. covalent modifications to protein structure after its translation. It is now known that there are over 200 PTM types that modulate protein activity in eukaryotic organisms by acting as molecular switches which turn on and off protein function, stabilize it or target for destruction or determine its cellular location. The objective is to carry out the following research activities: (Aim 1) Develop models for automated annotation of PTM sites (Aim 2) Analyze structural and functional properties of PTM sites (Aim 3) Integrate protein bioinformatics and proteomics to construct functional map of all major PTMs Intellectual Merit. This project introduces a novel framework of integrating protein bioinformatics and proteomics towards comprehensive understanding of the regulatory and signaling roles of PTMs. In addition to the new biological knowledge, this project will develop a set of tools that will enable accurate and efficient proteomics analysis and also aid experimental biologists in experimental design. Combinatorial explosion is currently the major hindrance in proteomics studies of PTMs and cellular processes they are involved in. Thus, the proposed prioritization of the proteomics searches by incorporating PTM prediction will not only make such studies realistic, but also enable identification of many new sites by decreasing the effective database size. PTMs frequently occur in unstructured protein regions that cannot be easily studied using traditional experimental methods (X-ray crystallography, NMR spectroscopy) and structural bioinformatics. Developing sequence based methods to predict PTM sites, integrating them into proteomics searches for verification, and investigating relationship between PTMs and genetic data may be crucial for understanding the molecular basis of many diseases, thus facilitating drug design and clinical therapy. The far-reaching promise of understanding life at a molecular level and advancing medical research can be fulfilled only through an integration of research and interdisciplinary education. To achieve this goal, the PI will extend and develop new courses at graduate and undergraduate level, will expose students to advanced education, and, through an active, rigorous and enthusiastic learning environment; train a generation of new experts and researchers who will be capable of making further advances. The teaching material and research results will be disseminated via our web site, by publishing papers in internationally recognized journals and by attending major conferences. The educational plan of this project will ensure participation of underrepresented minority and socioeconomic groups in research by partnering with the Office of Strategic Mentoring (OSM) and Alliances for Graduate and Professoriate Program (AGEP) at Indiana University. Two vital components of this plan are (i) attracting underrepresented students through OSM/AGEP and courses addressing data mining and bioinformatics, and (ii) retaining and promoting underrepresented students through committing funding, advising and mentoring.