Project description
Probing the backbone dynamics of high-mass proteins in solution
Proteins are made of amino acid building blocks linked together in a chain. The motion of the protein ‘backbone’ is fundamental to establishing the protein’s 3D shape and thus its activity. Given the critical role of protein backbone dynamics in almost all biological functions, they have been the subject of intense research. The most sensitive nuclear magnetic resonance (NMR) methods to address this are currently limited by mass constraints, making the most complex large proteins and their interactions inaccessible. Funded by the European Research Council, the bypassNMR project will overcome this barrier with an unprecedented combination of solid-state NMR and solution NMR, enabling a two-fold increase in the accessible molecular weight range.
Objective
My objective is to establish methodology expanding the detailed characterization and exploitation of backbone dynamics in complex proteins up to 80-100 kDa monomer molecular weight. Experimental elucidation of protein motion is imperative for fundamental understanding of enzymatic and regulatory features. However, with a limit of regularly around 40-50 kDa maximum total mass, the more complex targets of current scientific interest usually evade solution NMR backbone resonance assignment and remain inaccessible for the majority of sophisticated methods for protein dynamics. This paradigmatic shortcoming has led to serious limitations in the understanding and exploitation of protein dynamics.
Here I aim to achieve a two-fold expansion of the accessible molecular-weight range by an unprecedented hybrid strategy. Based on the unmatched prospects of 4D and 5D solid-state NMR (ssNMR) assignment data for a 2x72 kDa protein, I will establish proton-detected, higher-dimensionality ssNMR methodology as a powerful framework for NMR assignment in an unprecedented size range. Subsequently, developing strategies utilizing ssNMR assignments as a springboard to solution NMR will enable detailed characterization of those targets under close-to-physiological conditions. This fundamentally new BYPASS strategy will allow understanding of intramolecular regulatory circuits and coupled motional networks in innumerable, previously inaccessible complex proteins, with a transformative impact for dynamics, in particular allosteric regulation, in structural biology.
Fueled by my role as a key player in revolutionizing solid-state NMR via proton-detected, fast magic-angle spinning NMR methodology, my achievements will be paradigmatic for the accessibility and utility of dynamics for the structure-dynamics-function relationship of proteins and will have widespread consequences for a wide range of structural biology and downstream applications such as pharmacology and biotechnology.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsprotein folding
- natural sciencesbiological sciencesmolecular biologystructural biology
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Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Funding Scheme
ERC - Support for frontier research (ERC)Host institution
44227 Dortmund
Germany