Codon 129 polymorphism of the human prion protein influences the kinetics of amyloid formation

Lewis, Patrick A.; Tattum, M. Howard; Jones, Samantha; Bhelt, Daljit; Batchelor, Mark; Clarke, Anthony R.; Collinge, John; Jackson, Graham S.

doi:10.1099/vir.0.81630-0

Cited by 29 publications

(21 citation statements)

References 43 publications

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“…We note that if a small concentration of the CLHBH were present in vivo as a templating element, it might help rationalize the role of some of the mutations in the N-terminal region and in species dependent susceptibility or resistance to infection. Fibrillization 34 and oligomerization 35 experiments performed in vitro suggest that methionine at codon 129 is critical for aggregation. Assuming to this to be so for the fibrils of reference 9, we select uniquely one of the eight fibril models formed from CLHBHs and NLHBHs.…”

Section: Introductionmentioning

confidence: 99%

Left handed β helix models for mammalian prion fibrils

Kuneš

Clark

Cox

et al. 2008

Prion

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We propose models for in vitro grown mammalian prion protein fibrils based upon left handed beta helices formed both from the N-terminal and C-terminal regions of the proteinase resistant infectious prion core. The C-terminal threading onto a b-helical structure is almost uniquely determined by fixing the cysteine disulfide bond on a helix corner. In comparison to known left handed helical peptides, the resulting model structures have similar stability attributes including relatively low root mean square deviations in all atom molecular dynamics, substantial side-chainto-side-chain hydrogen bonding, good volume packing fraction, and low hydrophilic/hydrophobic frustration. For the N-terminus, we propose a new threading of slightly more than two turns, which improves upon the above characteristics relative to existing three turn b-helical models. The N-terminal and C-terminal beta helices can be assembled into eight candidate models for the fibril repeat units, held together by large hinge (order 30 residues) domain swapping, with three amenable to fibril promoting domain swapping via a small (five residue) hinge on the N-terminal side. Small concentrations of the metastable C-terminal b helix in vivo might play a significant role in templating the infectious conformation and in enhancing conversion kinetics for inherited forms of the disease and explain resistance (for canines) involving hypothesized coupling to the methionine 129 sulfur known to play a role in human disease.

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Section: Introductionmentioning

confidence: 99%

Left handed β helix models for mammalian prion fibrils

Kuneš

Clark

Cox

et al. 2008

Prion

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“…The M129V polymorphism has no measurable effects on the folding, dynamics or stability of PrP C . The assumption is that this polymorphism mediates its effects on prions propagation by inducing variations in the conformation of PrP Sc or its precursors or in the kinetics of their formation (Hosszu et al, 2004;Lewis et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Frequency distribution of PRNP polymorphisms in the Pakistani population

Imran

Mahmood

Hussain

et al. 2012

Gene

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“…These structures have previously been found to be characteristic features of aggregated amyloids and prion proteins, with the potential to serve as nuclei during PrP Sc propagation. Additionally, 129M homozygosity has the potential to influence the formation of ordered amyloid fibrils of partially denatured α-helical fold of the human PrP, in contrast to 129V homozygotes [30]. These 2 studies suggest that the human M/V polymorphism may act by influencing the kinetics of amyloid formation.…”

Section: The Critical Influence Of Prnp Codon 129 Polymorphism On Vcjmentioning

confidence: 99%

“…Confounding the discovery is that the stability, dynamics, metal ion binding capabilities, and 3D-structure of PrP c , with either 129M or 129V, is indistinguishable precluding a simple explanation based directly on a structural determinant [28,29,30]. However, one study has shown that 129M homozygosity is consistent with the formation of effective ‘steric-zippers' made up of a pair of self-complementary β-sheets devoid of water and possessing side chains with the potential to interdigitate [31].…”

Section: The Critical Influence Of Prnp Codon 129 Polymorphism On Vcjmentioning

confidence: 99%

The Genetics of Susceptibility to Variant Creutzfeldt-Jakob Disease

Saba

Booth

2013

Public Health Genomics

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The emergence of bovine spongiform encephalopathy (BSE) in cattle and, subsequently, its transmission to humans resulting in variant Creutzfeldt-Jakob disease (vCJD) in the UK has proved to be one of the major public health scares of the century. The oral route of infection, the long incubation period, and the incredible resistance of the transmissible infectious agent to various forms of decontamination poses unique challenges. Fortunately, despite extensive exposure of the UK population to contaminated meat, the size of the vCJD epidemic that has emerged since its initial detection is relatively low (225 worldwide). An explanation for this disparity is as yet incomplete, but the development of the disease is likely influenced by a number of factors including physical properties of the infectious agent, environmental factors such as the route and amount of exposure and individual susceptibility factors. This review focuses on current knowledge of the genetic factors that undoubtedly play a major role in influencing the development of vCJD. In terms of genetic susceptibility, the best characterised is the common single nucleotide polymorphism at codon 129 of the human prion protein gene (PRNP). Moreover, several other polymorphisms and mutations have been identified that may affect susceptibility as well as other important disease characteristics such as the highly variable prion disease incubation period.

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Codon 129 polymorphism of the human prion protein influences the kinetics of amyloid formation

Cited by 29 publications

References 43 publications

Left handed β helix models for mammalian prion fibrils

Left handed β helix models for mammalian prion fibrils

Frequency distribution of PRNP polymorphisms in the Pakistani population

The Genetics of Susceptibility to Variant Creutzfeldt-Jakob Disease

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