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High resolution tools to understand the functional role of protein intrinsic disorder

Final Report Summary - IDPBYNMR (High resolution tools to understand the functional role of protein intrinsic disorder)

The aim of the IDPbyNMR project was to train young researchers to carry out atomic resolution studies of intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) of structured proteins.
Recent evidence has shown that a large share of proteins gain functional advantages by remaining natively unstructured, either completely or partially, thus challenging well-established concepts in structural biology. In this frame NMR spectroscopy plays a strategic role to characterize at atomic resolution the highly dynamical properties of such “intrinsically disordered proteins”, and follow their (possible) reorganization by interacting with partners in environments as complex as whole cells. Understanding the functional role of intrinsically disordered protein states, which are involved in many biochemical processes at the basis of life, is changing the way we think about protein function with a tremendous impact in biomedical research and in the design of new drugs. This novel concept is not covered yet in mainstream textbooks on biochemistry and molecular biology, nor in standard college courses.
This emerging area of research requires fresh energies and ideas by highly talented and qualified young researchers. Thus, the main goal of the present project consisted in assembling a coordinated, interdisciplinary and inter-sectorial training program to form young researchers in the early stage of their careers (ESRs).
The scientific objective of the IDPbyNMR ITN consisted in the development of new tools for the high resolution investigation of IDPs within a research environment gathering top academic institutions, research centers and private companies. The ambitious training program stipulated in the Technical Annex for the project was respected in order to enable the ESRs to contribute to the specific research projects with innovative and creative ideas. The network provided a training program that offered additional opportunities with respect to the ones available locally at each site. Focus was not limited to the mere scientific and technological aspects and four of the organized Intensive Training Courses focused on Complementary Skills such as grant writing, project management, communication strategies, intellectual property rights, etc., offering the ESRs the foundations for a well-rounded and highly qualified career. As a proof of the success of the project, all fellows enrolled in the project contributed to publications which already appeared in peer reviewed journals, some of which with very good Impact Factor, and several other papers have already been submitted or are in preparation.
Research carried out by the students and network teams contributed to the following scientific highlights that considerably advanced the knowledge in the IDPs research field:
- Intrinsically disordered proteins, or protein regions, were suggested to play a key role in viral infection through short linear motives of viral proteins hijacking cell regulation. Several partners focused on the experimental characterization of viral IDPs through NMR and SAXS (CERM, CNRS-IBS, EMBL).
- Amyloids play a central role in several diseases, with NMR being a key tool for their atomic resolution characterization. GIOTTO, CERM and UCAM focused on sample preparation, on using solution and solid state NMR spectroscopy for their experimental characterization and on calculations of ensembles to test potential drugs.
- In-cell NMR is a growing scientific area as unique information at atomic resolution can in principle be accessed through NMR. VIB and BIO focused on this subject combining NMR with functional tests in-cell. Fast NMR methods were developed to cope with the limited lifetime of in-cell NMR samples (CNRS-IBS and CERM).
- The development of new NMR methods to study IDPs was carried out by Bruker, CERM and CNRS-IBS. The main strategies followed included further reducing NMR time to study kinetics, allow in-cell applications and/or design of new multiD NMR experiments as well as reducing the problem of extensive cross peak overlap by using inter residue correlations and exploiting aminoacid-selective strategies to simplify spectra.
- The development of general strategies to describe the residual structure in IDPs was pursued by CNRS-IBS, UCAM, EMBL.
- A database, the pEDB (www.pedb.vib) where the scientific community can deposit experimental data and structural ensembles of IDPs has been created as a result of the ITN (VIB and EMBL with contributions from CNRS-IBS, UCAM and CERM).
Already in winter 2013 it clearly emerged that the scientific outcome of the network formed a solid basis to propose new general principles on the behavior of IDPs and improved methodologies to study them. On occasion of the Supervisory Board meeting held in Hamburg on March 13 2013 it was suggested to gather contributions from all the IDPbyNMR partners in a book dedicated to the central scientific topic of the network. The book proposal submitted to Springer was enthusiastically accepted:
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The “IDPbyNMR book” is expected to be published in Spring 2015, with contributions from all the partners of the ITN, including the young fellows as main authors.
Besides being an important scientific goal, the publication of the IDPbyNMR book will represent a very important step for dissemination that will reinforce substantially the other activities carried out during the project life time. Among these it is worth mentioning the organization of the “IDPbyNMR final meeting”, which gathered the major experts in the field of IDPs and NMR, following extensive advertisement to the whole scientific community. Furthermore, the “IDPbyNMR video” was created to present in a simple way the major results of IDPbyNMR. It is included in YouTube, together with interviews to the major experts in the field. The video was realized with the support of an expert in scientific animations to reach not only the scientific community but also a broader public. In the first part of the video simple words and excellent graphics are used to describe the central research topic, to ensure dissemination of the results also the general public; in the second part of the video the research techniques and scientific highlights are introduced to attract the interest not only of specialists in the field but also of scientists coming from different areas (medicine, drug design etc.).
The IDPbyNMR project has been fundamental for laying the first bricks for an innovative Doctoral Training Program in an emerging field of research with high biomedical and pharmacological/pharmaceutical impact to form young brilliant researchers ready for the science of tomorrow.
The natural evolution of the IDPbyNMR project consists in disseminating the new concepts and ideas to larger and larger parts of the scientific community, in particular towards the biomedical area. For example, the area of cancer and drug discovery where these concepts are not radicated yet. In addition, since the field is still very young and very rapidly evolving, the new tools need to be further developed.
Therefore, the closing of the results of the IDPbyNMR project lay the basis for the next steps to achieve full benefit of the investments.