title: Surface charge of polyoxometalates modulates polymerization of the scrapie prion protein.
abstract: 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.
authors.affiliation: Institute for Neurodegenerative Diseases and Department of Neurology, University of California, San Francisco, CA 94143, USA. hwille@ind.ucsf.edu
authors.forename: Holger
authors.initials: H
authors.lastname: Wille
authors.forename: Maheswaran
authors.initials: M
authors.lastname: Shanmugam
authors.forename: Muralee
authors.initials: M
authors.lastname: Murugesu
authors.forename: Julian
authors.initials: J
authors.lastname: Ollesch
authors.forename: Gerald
authors.initials: G
authors.lastname: Stubbs
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Long
authors.forename: Jiri G
authors.initials: JG
authors.lastname: Safar
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Prusiner
mesh_terms: D000818:Animals; D011232:Chemical Precipitation; D003460:Crystallization; D051379:Mice; D018620:PrPSc Proteins / Q000737:chemistry* / Q000648:ultrastructure; D055503:Protein Multimerization; D013499:Surface Properties; D017973:Tungsten Compounds / Q000737:chemistry*
chemical_list: D018620:PrPSc Proteins; D017973:Tungsten Compounds