Cellular Heparan Sulfate Participates in the Metabolism of Prions

Ben-Zaken, Olga; Tzaban, Salit; Tal, Yuval; Horonchik, Lior; Esko, Jeffrey D.; Vlodavsky, Israël; Taraboulos, Albert

doi:10.1074/jbc.m301152200

Cited by 127 publications

(126 citation statements)

References 74 publications

(92 reference statements)

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“…supported by experiments showing that FabЈ fragments of some of these antibodies failed to immunoprecipitate PrPsc. This is not surprising taking into account that several proteins and polymers have already been shown to bind SAFs, including serum proteins (12), heparan sulfates (13,14), and nucleic acids (4,15). In addition, we show that a significant PrPsc immunoprecipitation can be obtained even with BSA-coated beads in appropriate conditions.…”

Section: Discussionmentioning

confidence: 75%

Selective and Efficient Immunoprecipitation of the Disease-associated Form of the Prion Protein Can Be Mediated by Nonspecific Interactions between Monoclonal Antibodies and Scrapie-associated Fibrils

Morel

Simon

Frobert

et al. 2004

Journal of Biological Chemistry

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Transmissible spongiform encephalopathies are characterized by the accumulation in brain tissues of an abnormal isoform of the prion protein named PrPsc, which is the only direct marker known for transmissible spongiform encephalopathies. Here we show that PrPsc can be specifically immunoprecipitated by using several monoclonal antibodies (mAbs) of various specificities independently of the properties of their binding site (paratope). These results strongly suggest that a significant proportion of mAbs can interact with PrPsc aggregates through nonspecific paratope-independent interactions allowing selective immunoprecipitation of PrPsc when these mAbs are immobilized on a polydisperse solid phase like microbeads.

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Section: Discussionmentioning

confidence: 75%

Selective and Efficient Immunoprecipitation of the Disease-associated Form of the Prion Protein Can Be Mediated by Nonspecific Interactions between Monoclonal Antibodies and Scrapie-associated Fibrils

Morel

Simon

Frobert

et al. 2004

Journal of Biological Chemistry

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“…Furthermore, the restricted range of neuronal and nonneuronal cell types that are susceptible to infection by prions also suggests the existence of prion propagation cofactors (11)(12)(13). Although no specific cofactors have been identified to date, several studies have shown that various polyanionic compounds, such as host-encoded RNA and proteoglycan molecules, appear to stimulate prion-seeded conversion of PrP C into PrP Sc molecules in vitro (10,(14)(15)(16)(17).…”

mentioning

confidence: 99%

Formation of native prions from minimal components in vitro

Deleault¹,

Harris²,

Rees³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

585

635

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The conformational change of a host protein, PrP C , into a disease-associated isoform, PrP Sc , appears to play a critical role in the pathogenesis of prion diseases such as Creutzfeldt–Jakob disease and scrapie. However, the fundamental mechanism by which infectious prions are produced in neurons remains unknown. To investigate the mechanism of prion formation biochemically, we conducted a series of experiments using the protein misfolding cyclic amplification (PMCA) technique with a preparation containing only native PrP C and copurified lipid molecules. These experiments showed that successful PMCA propagation of PrP Sc molecules in a purified system requires accessory polyanion molecules. In addition, we found that PrP Sc molecules could be formed de novo from these defined components in the absence of preexisting prions. Inoculation of samples containing either prion-seeded or spontaneously generated PrP Sc molecules into hamsters caused scrapie, which was transmissible on second passage. These results show that prions able to infect wild-type hamsters can be formed from a minimal set of components including native PrP C molecules, copurified lipid molecules, and a synthetic polyanion.

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“…Several lines of in vitro and in vivo evidences suggest that binding of PrP to GAG is important in the conversion process, and thus critical for pathogenesis (30)(31)(32)(33). PrP Sc in vivo contains GAG (34).…”

Section: Discussionmentioning

confidence: 99%

Human prion proteins with pathogenic mutations share common conformational changes resulting in enhanced binding to glycosaminoglycans

Yin

Pham

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Mutation in the prion gene PRNP accounts for 10 -15% of human prion diseases. However, little is known about the mechanisms by which mutant prion proteins (PrPs) cause disease. Here we investigated the effects of 10 different pathogenic mutations on the conformation and ligand-binding activity of recombinant human PrP (rPrP). We found that mutant rPrPs react more strongly with N terminus-specific antibodies, indicative of a more exposed N terminus. The N terminus of PrP contains a glycosaminoglycan (GAG)-binding motif. Binding of GAG is important in prion disease. Accordingly, all mutant rPrPs bind more GAG, and GAG promotes the aggregation of mutant rPrPs more efficiently than wild-type recombinant normal cellular PrP (rPrP C ). Furthermore, point mutations in PRNP also cause conformational changes in the region between residues 109 and 136, resulting in the exposure of a second, normally buried, GAG-binding motif. Importantly, brainderived PrP from transgenic mice, which express a pathogenic mutant with nine extra octapeptide repeats, also binds more strongly to GAG than wild-type PrP C . Thus, several rPrPs with distinct pathogenic mutations have common conformational changes, which enhance binding to GAG. These changes may contribute to the pathogenesis of inherited prion diseases.genetics ͉ structure

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Cellular Heparan Sulfate Participates in the Metabolism of Prions

Cited by 127 publications

References 74 publications

Selective and Efficient Immunoprecipitation of the Disease-associated Form of the Prion Protein Can Be Mediated by Nonspecific Interactions between Monoclonal Antibodies and Scrapie-associated Fibrils

Selective and Efficient Immunoprecipitation of the Disease-associated Form of the Prion Protein Can Be Mediated by Nonspecific Interactions between Monoclonal Antibodies and Scrapie-associated Fibrils

Formation of native prions from minimal components in vitro

Human prion proteins with pathogenic mutations share common conformational changes resulting in enhanced binding to glycosaminoglycans

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