Mapping key interactions in the dimerization process of HBHA from Mycobacterium tuberculosis, insights into bacterial agglutination

HBHA is a cell-surface protein implicated in the dissemination of Mycobacterium tuberculosis (Mtb) from the site of primary infection. Its N-terminal coiled-coil region is also involved in bacterial agglutination. However, despite the importance of HBHA dimerization in agglutination, protein regions involved in dimerization are hitherto not known. Here, we mapped these regions by coupling peptide synthesis, biochemical and computational analyses, and identified structural determinants for HBHA monomer-monomer recognition. Importantly, we obtained the first molecule able to induce HBHA dimer disaggregation at 37 degrees C, the typical growth temperature of Mtb. This result provides new opportunities towards the development of Mtb anti-aggregation molecules with therapeutic interest.