Gerald Stubbs
Last active: 2/15/2016

Surface charge of polyoxometalates modulates polymerization of the scrapie prion protein.

Wille H, Shanmugam M, Murugesu M, Ollesch J, Stubbs G, Long JR, Safar JG, Prusiner SB
Proc Natl Acad Sci U S A. 2009 106 (10): 3740-5

PMID: 19223590 · PMCID: PMC2656150 · DOI:10.1073/pnas.0812770106

Prions are composed solely of an alternatively folded isoform of the prion protein (PrP), designated PrP(Sc). N-terminally truncated PrP(Sc), denoted PrP 27-30, retains infectivity and polymerizes into rods with the ultrastructural and tinctorial properties of amyloid. We report here that some polyoxometalates (POMs) favor polymerization of PrP 27-30 into prion rods, whereas other POMs promote assembly of the protein into 2D crystals. Antibodies reacting with epitopes in denatured PrP 27-30 also bound to 2D crystals treated with 3 M urea. These same antibodies did not bind to either native PrP(Sc) or untreated 2D crystals. By using small, spherical POMs with Keggin-type structures, the central heteroatom was found to determine whether prion rods or 2D crystals were preferentially formed. An example of a Keggin-type POM with a phosphorous heteroatom is the phosphotungstate anion (PTA). Both PTA and a Keggin-type POM with a silicon heteratom have low-charge densities and favor formation of prion rods. In contrast, POMs with boron or hydrogen heteroatoms exhibiting higher negative charges encouraged 2D crystal formation. The 2D crystals of PrP 27-30 produced by selective precipitation with POMs were larger and more well ordered than those obtained by sucrose gradient centrifugation. Our findings argue that the negative charge of Keggin-type POMs determines the quaternary structure adopted by PrP 27-30. The mechanism by which POMs function in competing prion polymerization pathways--one favoring 2D crystals and the other, amyloid fibrils--remains to be established.

MeSH Terms (8)

Animals Chemical Precipitation Crystallization Mice Protein Multimerization PrPSc Proteins Surface Properties Tungsten Compounds

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