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The Prion Switch Unravelled
Author(s) -
Salzano Giulia,
Tran Thanh Hoa,
Giachin Gabriele,
Benetti Federico,
D'Angelo Paola,
Legname Giuseppe
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.564.13
Subject(s) - gene isoform , chemistry , scrapie , point mutation , prion protein , mutation , biophysics , x ray absorption spectroscopy , crystallography , absorption spectroscopy , biology , biochemistry , gene , medicine , physics , disease , quantum mechanics
The post‐translational conversion of the cellular prion protein (PrP C ) into the misfolded, pathogenic scrapie isoform (PrP Sc ) plays a key role in prion diseases. PrP C interacts with metal ions, in particular copper, through the octarepeat and non‐octarepeat (non‐OR) binding sites. In order to gain insights into the structural determinants involved in PrP Sc formation we investigated the effect of human PrP C (HuPrP) point mutations linked to the genetic form of human prion diseases. Previously, we carried out a structural investigation to determine the high resolution NMR structure of the truncated recHuPrP(90‐231) carrying the E219K polymorphism, the fCJD‐linked V210I and the GSS‐causing Q212P mutations. Such structural studies led to the preliminary conclusion that the structural disorder of the β2‐α2 loop region is a key pathological feature. Here, we evaluated the effect of the pathological mutations on the N‐terminal unstructured domain. We used synchrotron‐based X‐ray absorption structure (XAS) technique to study the coordination geometries of Cu(II) and Cu(I) at two pH values (5.5 and 7.0) in different recHuPrP(90‐231) constructs carrying pathological mutations. We clearly showed that mutations and pH exchanges cause a dramatic modification on both Cu(II) and Cu(I) coordinations in the non‐OR region. Our XAS study highlights the importance of the non‐OR region for prion conversion and proposes a cellular model in which PrP C coordinating copper with one His may be more prone to the conversion at acidic condition. Thus, the non‐OR region may act as the long‐sought‐after prion switch.