Structural effects of the highly protective V127 polymorphism on human prion protein

Laszlo L. P Hosszu, Rebecca Conners, Daljit Sangar, Mark Batchelor, Elizabeth B Sawyer, Stuart Fisher, Matthew J Cliff, Andrea M Hounslow, Katherine McAuley, R. Leo Brady, Graham S Jackson, Jan Bieschke, Jonathan P Waltho, John Collinge*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

2 Citations (Scopus)
43 Downloads (Pure)


Prion diseases, a group of incurable, lethal neurodegenerative disorders of mammals including humans, are caused by prions, assemblies of misfolded host prion protein (PrP). A single point mutation (G127V) in human PrP prevents prion disease, however the structural basis for its protective effect remains unknown. Here we show that the mutation alters and constrains the PrP backbone conformation preceding the PrP β-sheet, stabilising PrP dimer interactions by increasing intermolecular hydrogen bonding. It also markedly changes the solution dynamics of the β2-α2 loop, a region of PrP structure implicated in prion transmission and cross-species susceptibility. Both of these structural changes may affect access to protein conformers susceptible to prion formation and explain its profound effect on prion disease.
Original languageEnglish
Article number402
Number of pages13
JournalCommunications Biology
Publication statusPublished - 29 Jul 2020


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