Human prion protein: exploring the thermodynamic stability and structural dynamics of its pathogenic mutants.

ABSTRACT

Human familial prion diseases are known to be associated with different single-point mutants of the gene coding for prion protein with a primary focus at several locations of the globular domain. We have identified 12 different single-point pathogenic mutants of human prion protein (HuPrP) with the help of extensive perturbations/mutation technique at multiple locations of HuPrP sequence related to potentiality towards conformational disorders. Among these, some of the mutants include pathogenic variants that corroborate well with the literature reported proteins while majority include some unique single-point mutants that are either not explicitly studied early or studied for variants with different residues at the specific position. Primarily, our study sheds light on the unfolding mechanism of the above mentioned mutants in depth. Besides, we could identify some mutants under investigation that demonstrates not only unfolding of the helical structures but also extension and generation of the ß-sheet structures and or simultaneously have highly exposed hydrophobic surface which is assumed to be linked with the production of aggregate/fibril structures of the prion protein. Among the identified mutants, Q212E needs special attention due to its maximum exposure of hydrophobic core towards solvent and E200Q is found to be important due to its maximum extent of ß-content. We are also able to identify different respective structural conformations of the proteins according to their degree of structural unfolding and those conformations can be extracted and further studied in detail. Communicated by Ramaswamy H. Sarma.