Structural basis for the protective effect of the human prion protein carrying the dominant-negative E219K polymorphism

2012 ◽  
Vol 446 (2) ◽  
pp. 243-251 ◽  
Author(s):  
Ivana Biljan ◽  
Gabriele Giachin ◽  
Gregor Ilc ◽  
Igor Zhukov ◽  
Janez Plavec ◽  
...  
Keyword(s):  
Prion Protein ◽  
Structural Changes ◽  
Terminal Segment ◽  
Dominant Negative ◽  
Structural Basis ◽  
Experimental Conditions ◽  
Nmr Structures ◽  
Jakob Disease ◽  
Human Prion Protein ◽  
Prion Conversion

The most common form of prion disease in humans is sCJD (sporadic Creutzfeldt–Jakob disease). The naturally occurring E219K polymorphism in the HuPrP (human prion protein) is considered to protect against sCJD. To gain insight into the structural basis of its protective influence we have determined the NMR structure of recombinant HuPrP (residues 90–231) carrying the E219K polymorphism. The structure of the HuPrP(E219K) protein consists of a disordered N-terminal tail (residues 90–124) and a well-structured C-terminal segment (residues 125–231) containing three α-helices and two short antiparallel β-strands. Comparison of NMR structures of the wild-type and HuPrPs with pathological mutations under identical experimental conditions revealed that, although the global architecture of the protein remains intact, replacement of Glu219 with a lysine residue introduces significant local structural changes. The structural findings of the present study suggest that the protective influence of the E219K polymorphism is due to the alteration of surface charge distribution, in addition to subtle structural rearrangements localized within the epitopes critical for prion conversion.

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

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Laszlo L. P. Hosszu ◽  
Rebecca Conners ◽  
Daljit Sangar ◽  
Mark Batchelor ◽  
Elizabeth B. Sawyer ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Structural Changes ◽  
Prion Diseases ◽  
Single Point ◽  
Structural Basis ◽  
Single Point Mutation ◽  
Solution Dynamics ◽  
Human Prion Protein ◽  
Prion Transmission

AbstractPrion 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.

scholarly journals Sensitive protein misfolding cyclic amplification of sporadic Creutzfeldt–Jakob disease prions is strongly seed and substrate dependent

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maxime Bélondrade ◽  
Simon Nicot ◽  
Charly Mayran ◽  
Lilian Bruyere-Ostells ◽  
Florian Almela ◽  
...  
Keyword(s):  
Prion Protein ◽  
Protein Misfolding ◽  
Protein Misfolding Cyclic Amplification ◽  
Bank Voles ◽  
Substrate Dependence ◽  
Brain Extracts ◽  
Jakob Disease ◽  
Human Prion Protein

AbstractUnlike variant Creutzfeldt–Jakob disease prions, sporadic Creutzfeldt–Jakob disease prions have been shown to be difficult to amplify in vitro by protein misfolding cyclic amplification (PMCA). We assessed PMCA of pathological prion protein (PrPTSE) from 14 human sCJD brain samples in 3 substrates: 2 from transgenic mice expressing human prion protein (PrP) with either methionine (M) or valine (V) at position 129, and 1 from bank voles. Brain extracts representing the 5 major clinicopathological sCJD subtypes (MM1/MV1, MM2, MV2, VV1, and VV2) all triggered seeded PrPTSE amplification during serial PMCA with strong seed- and substrate-dependence. Remarkably, bank vole PrP substrate allowed the propagation of all sCJD subtypes with preservation of the initial molecular PrPTSE type. In contrast, PMCA in human PrP substrates was accompanied by a PrPTSE molecular shift during heterologous (M/V129) PMCA reactions, with increased permissiveness of V129 PrP substrate to in vitro sCJD prion amplification compared to M129 PrP substrate. Combining PMCA amplification sensitivities with PrPTSE electrophoretic profiles obtained in the different substrates confirmed the classification of 4 distinct major sCJD prion strains (M1, M2, V1, and V2). Finally, the level of sensitivity required to detect VV2 sCJD prions in cerebrospinal fluid was achieved.

Examination of the human prion protein-like gene Doppel for genetic susceptibility to sporadic and variant Creutzfeldt–Jakob disease

2000 ◽  
Vol 290 (2) ◽  
pp. 117-120 ◽  
Author(s):  
Simon Mead ◽  
Jonathan Beck ◽  
Andrew Dickinson ◽  
Elizabeth M.C Fisher ◽  
John Collinge
Keyword(s):  
Genetic Susceptibility ◽  
Prion Protein ◽  
Jakob Disease ◽  
Human Prion Protein

Intracerebroventricular delivery of dominant negative prion protein in a mouse model of iatrogenic Creutzfeldt-Jakob disease after dura graft transplantation

2006 ◽  
Vol 402 (3) ◽  
pp. 222-226 ◽  
Author(s):  
Kazuhide Furuya ◽  
Nobutaka Kawahara ◽  
Yoshio Yamakawa ◽  
Hitaru Kishida ◽  
Naomi S. Hachiya ◽  
...  
Keyword(s):  
Mouse Model ◽  
Prion Protein ◽  
Dominant Negative ◽  
Jakob Disease

scholarly journals Chronic wasting disease and atypical forms of bovine spongiform encephalopathy and scrapie are not transmissible to mice expressing wild-type levels of human prion protein

2012 ◽  
Vol 93 (7) ◽  
pp. 1624-1629 ◽  
Author(s):  
Rona Wilson ◽  
Chris Plinston ◽  
Nora Hunter ◽  
Cristina Casalone ◽  
Cristiano Corona ◽  
...  
Keyword(s):  
Bovine Spongiform Encephalopathy ◽  
Prion Protein ◽  
Chronic Wasting Disease ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Wild Type ◽  
Wasting Disease ◽  
Spongiform Encephalopathies ◽  
Jakob Disease ◽  
Human Prion Protein

The association between bovine spongiform encephalopathy (BSE) and variant Creutzfeldt–Jakob disease (vCJD) has demonstrated that cattle transmissible spongiform encephalopathies (TSEs) can pose a risk to human health and raises the possibility that other ruminant TSEs may be transmissible to humans. In recent years, several novel TSEs in sheep, cattle and deer have been described and the risk posed to humans by these agents is currently unknown. In this study, we inoculated two forms of atypical BSE (BASE and H-type BSE), a chronic wasting disease (CWD) isolate and seven isolates of atypical scrapie into gene-targeted transgenic (Tg) mice expressing the human prion protein (PrP). Upon challenge with these ruminant TSEs, gene-targeted Tg mice expressing human PrP did not show any signs of disease pathology. These data strongly suggest the presence of a substantial transmission barrier between these recently identified ruminant TSEs and humans.

scholarly journals NMR structures of three single-residue variants of the human prion protein

2000 ◽  
Vol 97 (15) ◽  
pp. 8340-8345 ◽  
Author(s):  
L. Calzolai ◽  
D. A. Lysek ◽  
P. Guntert ◽  
C. von Schroetter ◽  
R. Riek ◽  
...  
Keyword(s):  
Prion Protein ◽  
Nmr Structures ◽  
Human Prion Protein

scholarly journals Experimental Verification of a Traceback Phenomenon in Prion Infection

2010 ◽  
Vol 84 (7) ◽  
pp. 3230-3238 ◽  
Author(s):  
Atsushi Kobayashi ◽  
Nobuyuki Sakuma ◽  
Yuichi Matsuura ◽  
Shirou Mohri ◽  
Adriano Aguzzi ◽  
...  
Keyword(s):  
Prion Protein ◽  
Specific Antibody ◽  
Brain Homogenate ◽  
Mobility Patterns ◽  
Prolonged Incubation ◽  
Prion Infection ◽  
Jakob Disease ◽  
Human Prion Protein ◽  
First Time

ABSTRACT The clinicopathological phenotypes of sporadic Creutzfeldt-Jakob disease (sCJD) correlate with the allelotypes (M or V) of the polymorphic codon 129 of the human prion protein (PrP) gene and the electrophoretic mobility patterns of abnormal prion protein (PrPSc). Transmission of sCJD prions to mice expressing human PrP with a heterologous genotype (referred to as cross-sequence transmission) results in prolonged incubation periods. We previously reported that cross-sequence transmission can generate a new prion strain with unique transmissibility, designated a traceback phenomenon. To verify experimentally the traceback of sCJD-VV2 prions, we inoculated sCJD-VV2 prions into mice expressing human PrP with the 129M/M genotype. These 129M/M mice showed altered neuropathology and a novel PrPSc type after a long incubation period. We then passaged the brain homogenate from the 129M/M mouse inoculated with sCJD-VV2 prions into other 129M/M or 129V/V mice. Despite cross-sequence transmission, 129V/V mice were highly susceptible to these prions compared to the 129M/M mice. The neuropathology and PrPSc type of the 129V/V mice inoculated with the 129M/M mouse-passaged sCJD-VV2 prions were identical to those of the 129V/V mice inoculated with sCJD-VV2 prions. Moreover, we generated for the first time a type 2 PrPSc-specific antibody in addition to type 1 PrPSc-specific antibody and discovered that drastic changes in the PrPSc subpopulation underlie the traceback phenomenon. Here, we report the first direct evidence of the traceback in prion infection.

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