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

DOI: 10.1038/s42003-020-01126-6 DOI Help

Authors: Laszlo L. P. Hosszu (MRC Prion Unit at UCL) , Rebecca Conners (MRC Prion Unit at UCL; University of Bristol) , Daljit Sangar (MRC Prion Unit at UCL) , Mark Batchelor (MRC Prion Unit at UCL) , Elizabeth B. Sawyer (MRC Prion Unit at UCL) , Stuart Fisher (Diamond Light Source) , Matthew J. Cliff (University of Manchester) , Andrea M. Hounslow (University of Sheffield) , Katherine Mcauley (Diamond Light Source) , R. Leo Brady (University of Bristol) , Graham S. Jackson (MRC Prion Unit at UCL) , Jan Bieschke (MRC Prion Unit at UCL) , Jonathan P. Waltho (University of Manchester; University of Sheffield) , John Collinge (MRC Prion Unit at UCL)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Communications Biology , VOL 3

State: Published (Approved)
Published: July 2020
Diamond Proposal Number(s): 4923 , 5969

Open Access Open Access

Abstract: 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.

Journal Keywords: Prion diseases; Solution-state NMR

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography

Documents:
s42003-020-01126-6.pdf

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