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. 2001 Apr 10;98(8):4334-6.
doi: 10.1073/pnas.071066598. Epub 2001 Mar 27.

A role for intermolecular disulfide bonds in prion diseases?

E Welker  1 , W J Wedemeyer, H A Scheraga
Affiliations

A role for intermolecular disulfide bonds in prion diseases?

E Welker et al. Proc Natl Acad Sci U S A. .

Abstract

The key event in prion diseases seems to be the conversion of the prion protein PrP from its normal cellular isoform (PrP(C)) to an aberrant "scrapie" isoform (PrP(Sc)). Earlier studies have detected no covalent modification in the scrapie isoform and have concluded that the PrP(C) --> PrP(Sc) conversion is a purely conformational transition involving no chemical reactions. However, a reexamination of the available biochemical data suggests that the PrP(C) --> PrP(Sc) conversion also involves a covalent reaction of the (sole) intramolecular disulfide bond of PrP(C). Specifically, the data are consistent with the hypothesis that infectious prions are composed of PrP(Sc) polymers linked by intermolecular disulfide bonds. Thus, the PrP(C) --> PrP(Sc) conversion may involve not only a conformational transition but also a thiol/disulfide exchange reaction between the terminal thiolate of such a PrP(Sc) polymer and the disulfide bond of a PrP(C) monomer. This hypothesis seems to account for several unusual features of prion diseases.

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Figures

Figure 1
Figure 1
(a) Depolymerization reaction in which a terminal thiolate of a disulfide-bonded polymer attacks the preceding intermolecular disulfide bond, producing a shortened polymer and a monomer with an intact intramolecular disulfide bond. (b) Polymerization reaction in which a terminal thiolate of the disulfide-bonded polymer attacks the intramolecular disulfide bond of the cellular form PrPC, lengthening the polymer. Presumably, the PrPC molecule is destabilized by its association to the scrapie-form polymer, and hence, its disulfide bond is not as well protected as in free solution. (c) Reduction of an intermolecular disulfide bond. Experiments have demonstrated that the rates of reshuffling and reduction depend strongly on the stability of the tertiary structure protecting the disulfide bond (–20).
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