Probing Early Misfolding Events in Prion Protein Mutants by NMR Spectroscopy

Molecules

Gabriele Giachin¹  Ivana Biljan²  Gregor Ilc³  Janez Plavec³ 

[1] Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Via Bonomea 265,Trieste I-34136, Italy; E-Mail:;Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102A, Zagreb HR-10000, Croatia; E-Mail:;Slovenian NMR Centre, National Institute of Chemistry, Hajdrihova 19, Ljubljana SI-1000, Slovenia; E-Mails:

关键词: prion protein;    prions;    genetic mutations;    polymorphisms;    prion diseases;    3D structure;    NMR spectroscopy;   

DOI  :  10.3390/molecules18089451

来源: mdpi

【 摘 要 】

The post-translational conversion of the ubiquitously expressed cellular form of the prion protein, PrP^C, into its misfolded and pathogenic isoform, known as prion or PrP^Sc, plays a key role in prion diseases. These maladies are denoted transmissible spongiform encephalopathies (TSEs) and affect both humans and animals. A prerequisite for understanding TSEs is unraveling the molecular mechanism leading to the conversion process whereby most α-helical motifs are replaced by β-sheet secondary structures. Importantly, most point mutations linked to inherited prion diseases are clustered in the C-terminal domain region of PrP^C and cause spontaneous conversion to PrP^Sc. Structural studies with PrP variants promise new clues regarding the proposed conversion mechanism and may help identify “hot spots” in PrP^C involved in the pathogenic conversion. These investigations may also shed light on the early structural rearrangements occurring in some PrP^C epitopes thought to be involved in modulating prion susceptibility. Here we present a detailed overview of our solution-state NMR studies on human prion protein carrying different pathological point mutations and the implications that such findings may have for the future of prion research.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland.