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

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

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

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,

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, 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 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.

Human prion proteins with pathogenic mutations share common conformational changes resulting in enhanced binding to glycosaminoglycans. Publishing Authors By Initials

S Yin,N Pham,S Yu,C Li,P Wong,B Chang,SC Kang,E Biasini,P Tien,DA Harris,MS Sy,

For similar biochemical phenomena, metabolism, and nutrition: biochemical phenomena: protein binding research abstracts see: biochemical phenomena, metabolism, and nutrition: biochemical phenomena: protein binding research

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

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Proceedings of the National Academy of Sciences of

VOLUME: 104

Page Numbers: 7546-51

Journal Abbreviation:

ISSN: 0027-8424

DAY: 24

MONTH: 04

YEAR: 2007

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

Number of References:

LANGUAGE: eng

NlmUniqueID: 7505876

Human prion proteins with pathogenic mutations share common conformational changes resulting in enhanced binding to glycosaminoglycans. Keywords Mesh Terms:

KEYWORDS: Protein Binding

MESH TERMS: pathogenicity

Chemical & Substance for Abstract: Human prion proteins with pathogenic mutations share common conformational changes resulting in enhanced binding to glycosaminoglycans. Information

Substance Name: Prions

Registry Number: 0

Grant and Affiliation Information for Human prion proteins with pathogenic mutations share common conformational changes resulting in enhanced binding to glycosaminoglycans.

AFFILIATION: Department of Pathology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.

Country: United States

AGENCY: United States NINDS

GRANT: NS-045981-01

ACRONYM: NS

MEDLINETA: Proc Natl Acad Sci U S A

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