The pH-Triggered Conversion of the PrPc to PrPsc

Guo-Ping      Zhou; Ri-Bo      Huang

doi:10.2174/15680266113139990003

Abstract

Transmissible spongiform encephalopathies (TSEs) are prion protein misfolding diseases that involve the accumulation of an abnormal β-sheet-rich prion protein aggregated form (PrP^sc) of the normal α- helix-rich prion protein (PrP^c) within the central nervous system (CNS) and other organs. On account of its large size and insolubility properties, characterization of PrP^c is quite difficult. A soluble intermediate, called PrP^β or β^o, exhibiting many of the same features as PrP^sc, can be generated using a combination of low pH and/or mild denaturing conditions. Here, we review the current knowledge on the following five issues relevant to the conversion mechanisms of PrP^c to PrP^sc : (1) How is the Stability of the Helical Structures in the Native PrP^c Related to the Primary Structure of the PrP^c (2) Why the Low pH Solution System is a Ideal Trigger of PrP^c to PrP^sc Conversion (3) How are the Structural and Dynamical Characteristics of the α-helixrich Intermediates Determined using NMR Data (4) How are the Premolten (PrP^α4 and PrP^αβ) and β-Oligomer (PrP^β) Intermediates Detected and Assayed, and (5) Can the Disordered N-terminal Domain be folded into the Structural Segment? Particularly, Chou’s wenxiang diagram (http://en.wikipedia.org/wiki/Wenxiang_diagram) was introduced for providing an intuitive picture. This review may help to further understand the prion protein misfolding mechanism.