Ligand binding promotes prion protein aggregation - Role of the octapeptide repeats

Shuiliang Yu, Shaoman Yin, Nancy Pham, Poki Wong, Shin Chung Kang, Robert B. Petersen, Chaoyang Li, Man Sun Sy

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Aggregation of the normal cellular prion protein, PrP, is important in the pathogenesis of prion disease. PrP binds glycosaminoglycan (GAG) and divalent cations, such as Cu2+ and Zn2+. Here, we report our findings that GAG and Cu2+ promote the aggregation of recombinant human PrP (rPrP). The normal cellular prion protein has five octapeptide repeats. In the presence of either GAG or Cu2+, mutant rPrPs with eight or ten octapeptide repeats are more aggregation prone, exhibit faster kinetics and form larger aggregates than wild-type PrP. When the GAG-binding motif, KKRPK, is deleted the effect of GAG but not that of Cu2+ is abolished. By contrast, when the Cu2+-binding motif, the octapeptide-repeat region, is deleted, neither GAG nor Cu2+ is able to promote aggregation. Therefore, the octapeptide-repeat region is critical in the aggregation of rPrP, irrespective of the promoting ligand. Furthermore, aggregation of rPrP in the presence of GAG is blocked with anti-PrP mAbs, whereas none of the tested anti-PrP mAbs block Cu2+-promoted aggregation. However, a mAb that is specific for an epitope at the N-terminus enhances aggregation in the presence of either GAG or Cu2+. Therefore, although binding of either GAG or Cu2+ promotes the aggregation of rPrP, their aggregation processes are different, suggesting multiple pathways of rPrP aggregation.

Original languageEnglish (US)
Pages (from-to)5564-5575
Number of pages12
JournalFEBS Journal
Volume275
Issue number22
DOIs
StatePublished - Nov 1 2008
Externally publishedYes

Fingerprint

Glycosaminoglycans
Agglomeration
Ligands
Prions
Prion Proteins
Prion Diseases
Divalent Cations
Epitopes
Kinetics

Keywords

  • Aggregation
  • Copper
  • Glycosaminoglycan
  • Octapeptide repeat
  • Prion

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Yu, S., Yin, S., Pham, N., Wong, P., Kang, S. C., Petersen, R. B., ... Sy, M. S. (2008). Ligand binding promotes prion protein aggregation - Role of the octapeptide repeats. FEBS Journal, 275(22), 5564-5575. https://doi.org/10.1111/j.1742-4658.2008.06680.x

Ligand binding promotes prion protein aggregation - Role of the octapeptide repeats. / Yu, Shuiliang; Yin, Shaoman; Pham, Nancy; Wong, Poki; Kang, Shin Chung; Petersen, Robert B.; Li, Chaoyang; Sy, Man Sun.

In: FEBS Journal, Vol. 275, No. 22, 01.11.2008, p. 5564-5575.

Research output: Contribution to journalArticle

Yu, S, Yin, S, Pham, N, Wong, P, Kang, SC, Petersen, RB, Li, C & Sy, MS 2008, 'Ligand binding promotes prion protein aggregation - Role of the octapeptide repeats', FEBS Journal, vol. 275, no. 22, pp. 5564-5575. https://doi.org/10.1111/j.1742-4658.2008.06680.x
Yu, Shuiliang ; Yin, Shaoman ; Pham, Nancy ; Wong, Poki ; Kang, Shin Chung ; Petersen, Robert B. ; Li, Chaoyang ; Sy, Man Sun. / Ligand binding promotes prion protein aggregation - Role of the octapeptide repeats. In: FEBS Journal. 2008 ; Vol. 275, No. 22. pp. 5564-5575.
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