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 journalArticlepeer-review

22 Scopus citations


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
Pages (from-to)5564-5575
Number of pages12
JournalFEBS Journal
Issue number22
StatePublished - Nov 2008


  • Aggregation
  • Copper
  • Glycosaminoglycan
  • Octapeptide repeat
  • Prion


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