Pathogenic Mutations in the Hydrophobic Core of the Human Prion Protein Can Promote Structural Instability and Misfolding

Kamp, Marc W. van der; Daggett, Valerie

doi:10.1016/j.jmb.2010.09.060

Cited by 101 publications

(116 citation statements)

References 72 publications

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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: 91%

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: 91%

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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“…The latter type of pathogenic mutation has been found in at least 28 different locations, and effects on protein stability, misfolding as well as cellular processing and function are reported [123]. MD simulations can be used to study the effect of these mutations on protein conformation and stability, particularly for the 24 mutations that are found in the C-terminal folded domain of human PrP [124][125][126]. Structural biology can also offer insights into the structural effect of pathogenic mutations [75,127] (see also chapter Y by Surewicz et al).…”

Section: The Effect Of Pathogenic Mutationsmentioning

confidence: 99%

“…To investigate the influence of the disease-related mutations in the hydrophobic core on the conformation and dynamics of recPrP, Van der Kamp and Daggett recently performed extensive MD simulations [126]. In a comparison of three 50 ns runs for each mutant with equivalent simulations of WT human PrP (res.…”

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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“…The increased flexibility in the C-terminal of helix 2, the H2-H3 loop, residues 216-221 and a region covering residues 126-152 in the mutant structure in our simulation present a likely starting point for structural conversion in PrP. Other simulations have shown how the instability of point mutation is related to the loss of stability in the core domain of PrP (Van der Kamp & Daggett 2010).…”

Section: Resultsmentioning

confidence: 59%

Mutation in a valine residue induces drastic changes in 3D structure of human prion protein

Behmard

Abdolmaleki

Barzegari

2012

Frontiers in Life Science

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Misfolding and aggregation of the prion protein (PrP) result in prion diseases, which can occur infectiously, genetically and sporadically in humans. V210I is one of many disease-associated missense mutants of PrP, which occurs within the hydrophobic core of the protein. In the present study, we have performed molecular dynamic simulations of this PrP mutant in order to compare its dynamics and structural conformations with those of the wild-type PrP. Performed simulations illuminate the changes that occur when valine is substituted by isoleucine at position 210 of PrP. Changes can occur in helix 1 (H1), helix 2 (H2), helix 3 (H3) and around the mutation site. The V 210I mutation, especially, leads to increased flexibility in parts of the H1, H2, H3 structures that are normally stable. Overall, V 210I mutation in the hydrophobic core significantly affects the dynamics and stability of PrP. The simultaneous changes in different secondary structure elements together with perturbations in the hydrophobic core induce the drastic changes in the overall 3D structure of human prion protein.

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Pathogenic Mutations in the Hydrophobic Core of the Human Prion Protein Can Promote Structural Instability and Misfolding

Cited by 101 publications

References 72 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

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

Mutation in a valine residue induces drastic changes in 3D structure of human prion protein

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