CAREER: Bioinformatics of Protein Post-Translational Modifications

Indiana University, Bloomington IN

Investigators

Abstract

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.