Institut de Biologie StructuraleGrenoble / France

ERC Advanced Grant 2019 for Martin Blackledge

The European Research Council (ERC) has awarded an "Advanced Grant" to Martin Blackledge, group leader of the Institut de Biologie Structurale (IBS - CEA/CNRS/UGA mixed research unit), for his project on the atomic resolution description of highly dynamic molecular assemblies and their role in viral replication.

Martin Blackledge is FDP group leader and Deputy Director at the IBS in Grenoble. His project entitled "DynamicAssemblies" will receive € 2.5 million financial support from the ERC over 5 years. Scientific excellence at European level is one of the main criteria for the selection of these awards dedicated to ground-breaking, high-risk projects presented by active leading Principal Investigators with a track-record of significant research achievements in the last 10 years.

Martin Blackledge studied physics at the University of Manchester and received his doctorate (D. Phil) in 1987 under the direction of Professor George Radda at the University of Oxford developing techniques for biomolecular NMR spectroscopy in vivo. In 1989 he received a Royal Society Fellowship to work at the ETH Zürich under the supervision of Professor Richard Ernst (Nobel prize for chemistry 1991) where he first started to develop methods to study biomolecular dynamics by NMR. Having discovered the beauty of the Alps, he decided to continue this work at the Institut de Biologie Structurale (CEA/CNRS/UGA) in Grenoble where he has headed the “Protein Dynamics and Flexibility by NMR” group since 2007.

The primary research interest of the Blackledge group is the study of protein dynamics by NMR, often combined with complementary biophysical techniques and advanced molecular simulation, to characterize the role of conformational flexibility in biological function on a broad range of time and length scales, from molecular recognition dynamics in folded proteins, to reorganizational dynamics of large multi-domain assemblies exhibiting extensive protein disorder to the study of fundamental physics underlying protein dynamics. He has published over 200 articles in this field. Most recently his group uses these techniques to describe highly flexible or intrinsically disordered proteins (IDPs), to map the thermodynamics and kinetics of their interaction trajectories at atomic resolution, and to determine the relationship between their dynamic behaviour and functional mechanism.

What is this project "DynamicAssemblies" about ?

IDPs are present throughout all known proteomes, playing important roles in functional mechanisms in all aspects of biology. Many molecular assemblies comprise highly dynamic components that are functionally essential. The elaboration of time-resolved, atomic resolution descriptions of the interaction trajectories of such highly disordered complexes, comprising both folded and disordered domains, is extremely challenging, requiring the development of adapted methodologies that can account for their intrinsic flexibility.
The project will in particular describe the structural and dynamic behaviour of highly disordered viral replication machines, including pre- and post-nucleocapsid assembly complexes, their interaction kinetics with host and viral partners, the effects of post-translational modifications, their assembly and functional mechanisms. The project will also identify the role of these IDPs in functional liquid droplets that provide a highly efficient means to spatially and temporally control essential molecular processes.
NMR spectroscopy is an exquisitely sensitive tool for studying highly dynamic molecular systems, allowing precise characterization of local and long-range conformational dynamics of IDPs and their complexes at atomic resolution. Ongoing development of NMR-based methods, combined with advances in fluorescence spectroscopy, cryoEM and SAS, underpinned by parallel developments in molecular simulation to ensure the necessary theoretical framework, will provide the essential tools to investigate the functional mechanisms of these previously inaccessible complexes.

Keywords
Protein dynamics, NMR, intrinsically disordered proteins, phase separation, paramyxovirus, measles, nucleocapsid, self-assembly, molecular dynamics simulation, fluorescence

Amount of the award
€2.5 million for five years