Prion diseases are fatal neurodegenerative disorders linked to the deposition of the abnormal prion protein isoform called PrPSc or prion. The key molecular events triggering the diseases are the conformational changes from the normal cellular alpha-helical prion protein PrPC to the pathological beta-sheet enriched PrPSc. Therefore, understanding the mechanism and factors underlying the conversion process is essential to find possible diagnostic tools and treatments. Copper has long been known to correlate with neurodegenerative dysfunctions; PrPC is a copper binding protein via histidine residues in the highly conserved octapeptide repeats (OR) and the non-OR region located in the disordered N-terminal tail of the protein. The role of copper in facilitating protein aggregation and disease progression remains elusive. This study describes the impact of histidine residues on prion replication. By analyzing mouse PrP constructs that carry artificial mutations at histidines in the OR and non-OR, we provide cell evidence for the critical role of the non-OR copper binding site at histidine 95 in prion conversion. We also contribute to better understanding of the mechanisms and primary sites for prion conversion and replication. Our findings establish a platform for further studies aimed at elucidating the role of the H95 mutant in de novo prion diseases when expressed in transgenic mice.
|Titolo:||Role of the Fifth Copper Binding Site in Prion Conversion|
|Autori:||Mai TP; Legname G|
|Digital Object Identifier (DOI):||10.1007/978-3-319-11776-8_63|
|Data di pubblicazione:||2015|
|Appare nelle tipologie:||4.1 Contribution in Conference proceedings|