Biology

Dr. Ishita Sengupta
National Centre for Biological Sciences, Bangalore

The misfolding and aggregation of the mostly α-helical and monomeric prion protein into β-rich aggregates is responsible for a class of fatal neurodegenerative diseases, together known as “transmissible spongiform encephalopathies”. Recent evidences suggest that the pathogenic agent in prion diseases need not be mature amyloid fibrils, and could as well be smaller oligomers.

            Using structural biology tools, solution NMR and FRET, we decipher the misfolding and oligomerization mechanism of the mouse prion protein, at low pH in the presence of physiological concentrations of salt. Our NMR data suggests that a crucial salt-bridge needs to be disrupted in the monomer before misfolding and oligomerization can commence. Moreover, we find that oligomer formation is rate-limited by association and not conformational change, but can be accelerated by salt.

            Our FRET data complement our NMR data by monitoring conformational changes in the monomer that accompany oligomerization. We find that α-helix to β-sheet conversion in the prion protein occurs in two stages: an early collapse, followed by a slow extension. It will be interesting to see in the future if this is a generic misfolding mechanism for other α-helical proteins as well.