Journal
CURRENT TOPICS IN MEDICINAL CHEMISTRY
Volume 13, Issue 10, Pages 1152-1163Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/15680266113139990003
Keywords
PrP; protein misfolding; NMR spectroscopy; CD; beta-oligomer; premolten globule state; salt-bridge network; Chou's wenxiang diagram
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Transmissible spongiform encephalopathies (TSEs) are prion protein misfolding diseases that involve the accumulation of an abnormal beta-sheet-rich prion protein aggregated form (PrPsc) of the normal alpha- helix-rich prion protein (PrPc) within the central nervous system (CNS) and other organs. On account of its large size and insolubility properties, characterization of PrPsc is quite difficult. A soluble intermediate, called PrP beta or beta(o), exhibiting many of the same features as PrPsc, 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 PrPc to PrPsc : (1) How is the Stability of the Helical Structures in the Native PrPc Related to the Primary Structure of the PrPc (2) Why the Low pH Solution System is a Ideal Trigger of PrPc to PrPsc Conversion (3) How are the Structural and Dynamical Characteristics of the alpha-helix-rich Intermediates Determined using NMR Data (4) How are the Premolten (PrP alpha 4 and PrP alpha beta) and beta-Oligomer (PrP beta) 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.
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