Oligopeptide-Mediated Stabilization of the α-Helix of a Prion Protein Peptide

The inherited prion diseases such as Gerstmann-Sträussler-Scheinker syndrome (GSS) are linked to point mutations in the gene coding for the cellular isoform of the prion protein (PrPC). One particular point mutation A117V (Ala117 → Val) is linked to a variable pathology that usually includes deposition of neurofibrillary tangles. A prion protein peptide carrying this point mutation [PrP106-126(117V)] was generated and compared with a peptide based on the normal human sequence [PrP106-126(117A)]. The inclusion of this point mutation increased the toxicity of PrP106-126 which could be linked to an increased β-sheet content. An assay of microtubule formation in the presence of tau indicated that PrP106-126 decreased the rate of microtubule formation that could be related to the displacement of tau. PrP106-126 carrying the 117 mutation was more efficient at inhibiting microtubule formation. These results suggest a possible mechanism of toxicity for protein carrying this mutation via destabilization of the cytoskeleton and deposition of tau in filaments, as observed in GSS.

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Prion protein-overexpressing cells show altered response to a neurotoxic prion protein peptide

Journal of Neuroscience Research ◽

10.1002/(sici)1097-4547(19981101)54:3<331::aid-jnr4>3.0.co;2-k ◽

1998 ◽

Vol 54 (3) ◽

pp. 331-340 ◽

Cited By ~ 24

Author(s):

David R. Brown

Keyword(s):

Prion Protein ◽

Altered Response ◽

Prion Protein Peptide

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A human prion protein peptide (PrP59–91) protects against copper neurotoxicity

Molecular Psychiatry ◽

10.1038/sj.mp.4001414 ◽

2003 ◽

Vol 8 (10) ◽

pp. 835-835 ◽

Cited By ~ 2

Author(s):

M A Chacón ◽

M I Barría ◽

R Lorca ◽

J P Huidobro-Toro ◽

N C Inestrosa

Keyword(s):

Prion Protein ◽

Human Prion Protein ◽

Prion Protein Peptide

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Electrostatics in the stability and misfolding of the prion protein: salt bridges, self energy, and solvationThis paper is one of a selection of papers published in this special issue entitled “Canadian Society of Biochemistry, Molecular & Cellular Biology 52nd Annual Meeting — Protein Folding: Principles and Diseases” and has undergone the Journal's usual peer review process.

Biochemistry and Cell Biology ◽

10.1139/o09-180 ◽

2010 ◽

Vol 88 (2) ◽

pp. 371-381 ◽

Cited By ~ 23

Author(s):

Will C. Guest ◽

Neil R. Cashman ◽

Steven S. Plotkin

Keyword(s):

Prion Protein ◽

Electrostatic Potential ◽

Peer Review Process ◽

Salt Bridge ◽

Salt Bridges ◽

Self Energy ◽

Low Dielectric ◽

The Stability ◽

Α Helix ◽

Electrostatic Potential Energy

Using a recently developed mesoscopic theory of protein dielectrics, we have calculated the salt bridge energies, total residue electrostatic potential energies, and transfer energies into a low dielectric amyloid-like phase for 12 species and mutants of the prion protein. Salt bridges and self energies play key roles in stabilizing secondary and tertiary structural elements of the prion protein. The total electrostatic potential energy of each residue was found to be invariably stabilizing. Residues frequently found to be mutated in familial prion disease were among those with the largest electrostatic energies. The large barrier to charged group desolvation imposes regional constraints on involvement of the prion protein in an amyloid aggregate, resulting in an electrostatic amyloid recruitment profile that favours regions of sequence between α helix 1 and β strand 2, the middles of helices 2 and 3, and the region N-terminal to α helix 1. We found that the stabilization due to salt bridges is minimal among the proteins studied for disease-susceptible human mutants of prion protein.

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Cellular effects of a neurotoxic prion protein peptide are related to its ?-sheet content

Neuroscience Research Communications ◽

10.1002/(sici)1520-6769(199809/10)23:2<119::aid-nrc6>3.0.co;2-g ◽

1998 ◽

Vol 23 (2) ◽

pp. 119-128 ◽

Cited By ~ 16

Author(s):

David R. Brown ◽

Martin Pitschke ◽

Detlev Riesner ◽

Hans A. Kretzschmar

Keyword(s):

Prion Protein ◽

Cellular Effects ◽

Prion Protein Peptide

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Aggregation of prion protein with insertion mutations is proportional to the number of inserts

Biochemical Journal ◽

10.1042/bj20061592 ◽

2007 ◽

Vol 403 (2) ◽

pp. 343-351 ◽

Cited By ~ 17

Author(s):

Shuiliang Yu ◽

Shaoman Yin ◽

Chaoyang Li ◽

Poki Wong ◽

Binggong Chang ◽

...

Keyword(s):

Prion Protein ◽

Prion Diseases ◽

Biochemical Properties ◽

Mutant Protein ◽

Insertion Mutant ◽

Wild Type ◽

Mutant Proteins ◽

Severity Of The Disease ◽

Α Helix ◽

Insertion Mutations

Mutation in the prion gene, PRNP, accounts for approx. 10–15% of human prion diseases. However, little is known about the mechanisms by which a mutant prion protein (PrP) causes disease. We compared the biochemical properties of a wild-type human prion protein, rPrPC (recombinant wild-type PrP), which has five octapeptide-repeats, with two recombinant human prion proteins with insertion mutations, one with three more octapeptide repeats, rPrP8OR, and the other with five more octapeptide repeats, rPrP10OR. We found that the insertion mutant proteins are more prone to aggregate, and the degree and kinetics of aggregation are proportional to the number of inserts. The octapeptide-repeat and α-helix 1 regions are important in aggregate formation, because aggregation is inhibited with monoclonal antibodies that are specific for epitopes in these regions. We also showed that a small amount of mutant protein could enhance the formation of mixed aggregates that are composed of mutant protein and wild-type rPrPC. Accordingly, rPrP10OR is also more efficient in promoting the aggregation of rPrPC than rPrP8OR. These findings provide a biochemical explanation for the clinical observations that the severity of the disease in patients with insertion mutations is proportional to the number of inserts, and thus have implications for the pathogenesis of inherited human prion disease.

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