Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
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Biochemical Analysis of Interaction between Kringle Domains of Plasminogen and Prion Proteins with Q167R Mutation

  • Lee, Jeongmin (Division of Zoonoses, Center for Immunology and Pathology, National Institute of Health, Korea Centers for Disease Control and Prevention) ;
  • Lee, Byoung Woo (Department of Genetic Engineering, Sungkyunkwan University) ;
  • Kang, Hae-Eun (Division of Foreign Animal Disease, Animal and Plant Quarantine Agency) ;
  • Choe, Kevine K. (Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University) ;
  • Kwon, Moosik (Department of Genetic Engineering, Sungkyunkwan University) ;
  • Ryou, Chongsuk (Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University)
  • Received : 2017.02.13
  • Accepted : 2017.03.08
  • Published : 2017.05.28
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Abstract

The conformational change of cellular prion protein ($PrP^C$) to its misfolded counterpart, termed $PrP^{Sc}$, is mediated by a hypothesized cellular cofactor. This cofactor is believed to interact directly with certain amino acid residues of $PrP^C$. When these are mutated into cationic amino acid residues, $PrP^{Sc}$ formation and prion replication halt in a dominant negative (DN) manner, presumably due to strong binding of the cofactor to mutated $PrP^C$, designated as DN PrP mutants. Previous studies demonstrated that plasminogen and its kringle domains bind to PrP and accelerate $PrP^{Sc}$ generation. In this study, in vitro binding analysis of kringle domains of plasminogen to Q167R DN mutant PrP (PrPQ167R) was performed in parallel with the wild type (WT) and Q218K DN mutant PrP (PrPQ218K). The binding affinity of PrPQ167R was higher than that of WT PrP, but lower than that of PrPQ218K. Scatchard analysis further indicated that, like PrPQ218K and WT PrP, PrPQ167R interaction with plasminogen occurred at multiple sites, suggesting cooperativity in this interaction. Competitive binding analysis using $\small{L}$-lysine or $\small{L}$-arginine confirmed the increase of the specificity and binding affinity of the interaction as PrP acquired DN mutations. Circular dichroism spectroscopy demonstrated that the recombinant PrPs used in this study retained the ${\alpha}$-helix-rich structure. The ${\alpha}$-helix unfolding study revealed similar conformational stability for WT and DN-mutated PrPs. This study provides an additional piece of biochemical evidence concerning the interaction of plasminogen with DN mutant PrPs.

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References

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