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

Shaoman Yin, Nancy Pham, Shuiliang Yu, Chaoyang Li, Poki Wong, Binggong Chang, Shin Chung Kang, Emiliano Biasini, Po Tien, David A. Harris, Man Sun Sy

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

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 (rPrPC). 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, brain-derived PrP from transgenic mice, which express a pathogenic mutant with nine extra octapeptide repeats, also binds more strongly to GAG than wild-type PrPC. 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.

Original languageEnglish (US)
Pages (from-to)7546-7551
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number18
DOIs
StatePublished - May 1 2007
Externally publishedYes

Fingerprint

Glycosaminoglycans
Prion Diseases
Mutation
Prions
Mutant Proteins
Prion Proteins
Point Mutation
Human Activities
Transgenic Mice
Ligands
Antibodies
Brain
Genes

Keywords

  • Genetics
  • Structure

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Human prion proteins with pathogenic mutations share common conformational changes resulting in enhanced binding to glycosaminoglycans. / Yin, Shaoman; Pham, Nancy; Yu, Shuiliang; Li, Chaoyang; Wong, Poki; Chang, Binggong; Kang, Shin Chung; Biasini, Emiliano; Tien, Po; Harris, David A.; Sy, Man Sun.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 18, 01.05.2007, p. 7546-7551.

Research output: Contribution to journalArticle

Yin, Shaoman ; Pham, Nancy ; Yu, Shuiliang ; Li, Chaoyang ; Wong, Poki ; Chang, Binggong ; Kang, Shin Chung ; Biasini, Emiliano ; Tien, Po ; Harris, David A. ; Sy, Man Sun. / Human prion proteins with pathogenic mutations share common conformational changes resulting in enhanced binding to glycosaminoglycans. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 18. pp. 7546-7551.
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