Journal of Physical Chemistry & Biophysics
Open Access

Thermodynamic study at residue resolution of the unfolding and refolding process of H2H3 domain of prion protein

5^th International Conference on Physical and Theoretical Chemistry

October 11- 13, 2018 | Edinburgh, Scotland

Miquel Adrover, Joan Mas and Human Rezaei

University of Balearic Islands, Spain
French National Institute for Agricultural Research, France

Posters & Accepted Abstracts: J Phys Chem Biophys

Abstract :

Prion diseases are unique neurodegenerative diseases because their infectivity is mediated by the misfolding of the endogenous prion protein (PrPC) towards the formation of a β-sheet-enriched and aggregated form (PrPSC). PrPSC has been observed as amyloid plaques in brains, and its formation arise from a structural rearrangement from the helical PrPC to the pathological PrPSC, which is able to template and promote the conformational change on other PrPC. PrPC contains an unstructured N-terminal tail and a folded C-terminal domain formed by three helices (H1, H2 and H3) and a short-stranded β-sheet (S1 and S2). The structure of PrPSc has not been elucidated yet, although for a long time it was accepted that the region S1H1S2 was crucial for the β-sheet seeding and the PrPSC formation. However, in 2007 it was demonstrated that the fragment containing the helices H2H3 integrated the core of the amyloid fibrils. Later on, we proved that H2H3 fragment was: i) the only able to reproduce the oligomerization and the fibrilization pathways of PrP; ii) able to retain the native structure of PrP; and iii) able to interact with poly-lysine and avoid the cell infection. Hence, H2H3 could be the minimal region involved in the conformational change of PrP. Now we have done a step further trying to unveil the thermal unfolding/refolding pathways of H2H3. NMR spectroscopy revealed that folded and unfolded H2H3 display fast exchange equilibria. Moreover, 15N and 1HN chemical shifts were used to derive the thermodynamic parameters at residue level. Unfolding of H2H3 starts at the N-terminus of H3, followed by the C-terminus of H2 and by the C-terminus of H3. The N-terminus of H2 is the region with higher stability. Unfolding/refolding occurs through the same pathway for most of the residues, although some of them show hysteresis (N177, H180 or A208).

Biography :

E-mail: miquel.adrover@uib.es