Pathogenic Mutations Located in the Hydrophobic Core of the Prion Protein Interfere with Folding and Attachment of the Glycosylphosphatidylinositol Anchor

Kiachopoulos, Sophia; Bracher, A.; Winklhofer, Konstanze F.; Tatzelt, Jörg

doi:10.1074/jbc.m412525200

Cited by 42 publications

(39 citation statements)

References 49 publications

(61 reference statements)

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“…However, it is also possible that the apparent proteinase resistance of these mutants compared with wild-type proteins is caused by their relative insolubility in Triton X-100. These results are in agreement with similar findings for pathological PrP C mutants in different cell models (45)(46)(47)(48). However, it is important to note that the PK concentrations used in the current study are at least 5 times lower than those used to show resistance of the prion isoform associate with infection (49 -51), thus suggesting that a putative function of these proteins may not be affected by aggregation.…”

Section: Cf10 Cells Transfected With Wild-type and Mutated Murine Prpsupporting

confidence: 81%

Disease-associated Mutations in the Prion Protein Impair Laminin-induced Process Outgrowth and Survival

Machado

Beraldo

Santos

et al. 2012

Journal of Biological Chemistry

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Background: In addition to the toxicity mediated by prion protein misfolding, mechanisms associated with its loss-offunction in genetic prion diseases are unknown. Results: Neural cells expressing PrP C mutants associated with prion diseases present impaired laminin-mediated process outgrowth and survival. Conclusion: PrP C mutants show loss-of-function in neural cells. Significance: The impairment of prion protein functions may contribute to the etiology of prion diseases.

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Section: Cf10 Cells Transfected With Wild-type and Mutated Murine Prpsupporting

confidence: 81%

Disease-associated Mutations in the Prion Protein Impair Laminin-induced Process Outgrowth and Survival

Machado

Beraldo

Santos

et al. 2012

Journal of Biological Chemistry

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“…2A). This feature has been described previously for PrP pathogenic mutants with immature glycosylation (6,20,22,25,30,32,46,47). This stimulated us to study the glycosylation of PrP␣3M mutants, focusing on HaPrPDS as a model.…”

Section: Toxic Ctmprp Lacks Disulfide Bondmentioning

confidence: 99%

Failure of Prion Protein Oxidative Folding Guides the Formation of Toxic Transmembrane Forms

Lisa

Domingo

Martínez

et al. 2012

Journal of Biological Chemistry

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Background:In vivo folding could play an essential role in prion neurodegenerations. Results: Artificial mutants causing labile PrP folds when expressed in cells originate toxic CtmPrP featured by the absence of the intramolecular disulfide bond. Conclusion: Oxidative folding impairment facilitates the formation of the toxic PrP forms. Significance: Unveiling the mechanism facilitating the formation of toxic PrP forms is crucial for the understanding and prevention of prion disorders.The mechanism by which pathogenic mutations in the globular domain of the cellular prion protein (PrP C ) increase the likelihood of misfolding and predispose to diseases is not yet known. Differences in the evidences provided by structural and metabolic studies of these mutants suggest that in vivo folding could be playing an essential role in their pathogenesis. To address this role, here we use the single or combined M206S and M213S artificial mutants causing labile folds and express them in cells. We find that these mutants are highly toxic, fold as transmembrane PrP, and lack the intramolecular disulfide bond. When the mutations are placed in a chain with impeded transmembrane PrP formation, toxicity is rescued. These results suggest that oxidative folding impairment, as on aging, can be fundamental for the genesis of intracellular neurotoxic intermediates key in prion neurodegenerations.Prion disorders are dominant gain-of-function neurodegenerations whose pathogenesis is linked to misfolded forms of the cellular prion protein (PrP C ), 3 including the prion PrP Sc and the neurotoxic CtmPrP (1-4). PrPSc is an aggregated and proteaseresistant ␤-sheet-enriched conformer of PrP C , which self-perpetuates by the templating the conversion of cell surface PrP C (1, 4). In contrast, CtmPrP is an intracellular transmembrane form generated at the ER with neurotoxic properties (1,5,6). Despite that CtmPrP formation was associated with features of the ER translocation process several pathogenic mutations in the C-terminal domain such as H187R and E200K enhance its levels, suggesting a yet unexplored in vivo interplay between folding and the accumulation and action of this neurotoxic form (6 -8).Since the enunciation of the prion hypothesis, research has focused on the mechanism by which a native PrP C structure reorganizes and acquires self-propagative features like those of PrP Sc (9 -11). The PrP C native state was assigned to the fold adopted by the chain lacking the signal sequences and containing the disulfide bond and used as reference for testing the effect of pathogenic mutations and its conversion into active prions (10,(12)(13)(14)(15)(16). However, the in vivo folding of proteins segregating into the secretory route such as PrP is a complex process participated by the ER folding machinery. This machinery coordinates processing (signal sequences removal, addition of covalent modifications, binding of cofactors, etc.), avoids undesired aggregations, and permits the acquisition of correct structure. This global process involves m...

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“…In contrast, the significant instability and conformational changes observed for T183A and F198S, also observed in coarse-grained MD simulation of T183A [154], may indicate a different disease mechanism. Cell studies indicate that the instability of the globular fold interferes with GPI-anchor attachment and subsequent cellular processing [155,156]. In vivo, these mutations typically cause a prolonged duration of disease [157] and can lead to abnormal PrP Sc formation [158].…”

Section: Mutations In the Hydrophobic Corementioning

confidence: 99%

Molecular Dynamics as an Approach to Study Prion Protein Misfolding and the Effect of Pathogenic Mutations

Kamp

Daggett

2011

Topics in Current Chemistry

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Pathogenic Mutations Located in the Hydrophobic Core of the Prion Protein Interfere with Folding and Attachment of the Glycosylphosphatidylinositol Anchor

Cited by 42 publications

References 49 publications

Disease-associated Mutations in the Prion Protein Impair Laminin-induced Process Outgrowth and Survival

Disease-associated Mutations in the Prion Protein Impair Laminin-induced Process Outgrowth and Survival

Failure of Prion Protein Oxidative Folding Guides the Formation of Toxic Transmembrane Forms

Molecular Dynamics as an Approach to Study Prion Protein Misfolding and the Effect of Pathogenic Mutations

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