Functional mechanism of heparin-binding hemagglutinin adhesin from Mycobacterium tuberculosis

ended

Tuberculosis (TB) is one of the most aberrant causes of global mortality and the molecular mechanisms of its pathogenesis are not well understood. The extrapulmonary dissemination of TB involves requires a crucial virulence factor designated as heparin-binding haemaglutinin adhesin (HBHA). HBHA is a 28 kDa dimeric protein localised at the surface of the Mycobacterium tuberculosis (MTB) that binds dextran sulphate, dermatan sulphate, glycosaminoglycans and heparan-sulphate proteoglycans thus mediating the adhesion with epithelial cells and to extracellular matrix components. Despite a crucial role in the dissemination of TB, a key relevance as strong diagnostic antigen and as therapeutic target, there is currently limited understanding of the structure and mechanism of action of HBHA. The ambitious aim of this proposal is to characterise at high-resolution the mechanisms of function of HBHA in different phases of the life cycle of MTB. To achieve this ambitious target, we will carry out an integrated investigation of solution-state and solid-state NMR nuclear magnetic resonance (NMR) to acquire high-resolution data on the interaction of HBHA with membranes of MTB. The NMR experiments will be complemented with biophysical studies and mutagenesis to accurately define the relationship between structure, dynamics and function of HBHA. Our preliminary data suggest that this ambitious project comes at the most opportune time as we now have tools, materials and knowledge to resolve this important goal for biochemistry and reveal the propeties of a crucial molecule for the mechanism of extrapulmonary dissemination of TB.