Background and research interests
The Biomolecular NMR research group is part of the Inorganic and Organic Chemistry Department of the University of Barcelona but is physically located at the Barcelona Science Park, next to the NMR high field facility recognized as "Instalación Científico-Tecnológica Singular" (large scale facility) by the Spanish Government.
We use biophysical methods, specially NMR, as well as chemical biology, molecular biology, and computational approaches to study proteins involved in regulatory processes, for which dynamics is an essential component.
Intrinsically disordered proteins (IDPs) are essential for the regulation of eukaryotic organisms. Eukaryotic cells have to dynamically integrate multiple inputs and respond efficiently. Prokaryotic strategies, exemplified by the classical Lac operon, could not cope with the demands of cell cycle control or tissue formation.
Classical regulation mechanisms are based on variations on the “lock and key” paradigm, i.e. one key opens one door, even if the locks can be quite sophisticated. IDP-based regulation seems to be better described, conceptually, as a computer programs that decides in a given moment which doors can be opened by a card carrying a certain chip.
Our challenge is to discover the programming rules and actual programs that explain IDP function, thus going beyond the structure-function paradigm towards a new one focusing on information-function.
Disordered Regions of Src Family Kinases
We are currently studying the role of the intrinsically disordered Unique domain of human c-Src, a non-receptor protein tyrosine kinase involved in a large variety of signaling pathway, and that of other members of the Src Family of Kinases. This domain is responsible for the specificity between members of the c-Src kinase family.
The Unique domain forms, together with the SH4 and SH3 domains, a new functional regulatory unit.
SFKs are part of an important class of proteins that are anchored to the membrane surface by lipidated, intrinsically disordered proteins. We have put forward the hypothesis that these proteins define a boundary layer with intermediate properties between 2D and 3D that we call the Disordered Boundary of the Cell (DBC) .
Other research lines
Phosphatases. We have been studying for a long time the low molecular weight tyrosine phosphatase (lmw-PTP) that reverse the action of kinases and dephosphorylate and inactivate c-Src itself. We have used lmw-PTP as a model system to study weak self-association by NMR relaxation, hydrodynamic methods, 129Xe-NMR, Small Angle X-ray Scattering, drug design methods, and the effect of macromolecular crowding and cosolutes. We are currently also studying calcineurin, a calcium dependent, serine/threonine phosphatase.
Bacterial proteins and the regulation of bacterial pathogenicity. Increased resistance to antibiotics is a major threat to human health. Selective regulation of horizontally acquired genes increases the fitness of resistant bacteria. The Hha protein, acting as a co-regulator of H-NS, provides the required selectivity. Using structural and dynamic information we have provided key mechanistic insight in this process. Hha is a pleiotropic protein that is also part of a toxin-antitoxin system to regulate biofilms, another element of antibiotic resistance. The TomB-Hha system is based on a novel chemical mechanism that involves only transient interactions.
Methodology M.Pons is the scientific director of the Spanish National Large Scale NMR facility and the Biomolecular NMR group contributes to the development and implementation of new NMR methodology. In particular members of the group are working in Dynamic Nuclear Polarization and the properties of stable free radicals.
Funding
