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Biochemical Analysis of Interaction between Kringle Domains of Plasminogen and Prion Proteins with Q167R Mutation

Title
Biochemical Analysis of Interaction between Kringle Domains of Plasminogen and Prion Proteins with Q167R Mutation
Author
Choe, Kevin Kyungsik
Keywords
Prion protein; dominant negative mutant; cofactor; plasminogen; DOMINANT-NEGATIVE INHIBITION; CREUTZFELDT-JAKOB-DISEASE; NATURAL SCRAPIE; PRP GENOTYPE; SHEEP; PROPAGATION; BINDING; REPLICATION; GENE; ASSOCIATION
Issue Date
2017-05
Publisher
KOREAN SOC MICROBIOLOGY & BIOTECHNOLOGY
Citation
Journal of Microbiology and Biotechnology, v. 27, No. 5, Page. 1023-1031
Abstract
The conformational change of cellular prion protein (PrPC) to its misfolded counterpart, termed PrPSc, is mediated by a hypothesized cellular cofactor. This cofactor is believed to interact directly with certain amino acid residues of PrPC. When these are mutated into cationic amino acid residues, PrPSc formation and prion replication halt in a dominant negative(DN) manner, presumably due to strong binding of the cofactor to mutated PrPC, designated as DN PrP mutants. Previous studies demonstrated that plasminogen and its kringle domains bind to PrP and accelerate PrPSc 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 L-lysine or 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 α-helix-rich structure. The α-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.
URI
http://www.jmb.or.kr/journal/view.html?doi=10.4014/jmb.1702.02029http://repository.hanyang.ac.kr/handle/20.500.11754/103284
ISSN
1017-7825; 1738-8872
DOI
10.4014/jmb.1702.02029
Appears in Collections:
COLLEGE OF PHARMACY[E](약학대학) > PHARMACY(약학과) > Articles
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